{"gene":"BCL10","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1999,"finding":"BCL10 contains an N-terminal CARD domain that mediates homodimerization/oligomerization; CARD-mediated oligomerization is essential for both NF-κB activation and apoptosis induction. Wild-type BCL10 activates NF-κB and induces apoptosis, while C-terminal truncation mutants retain NF-κB activation but lose pro-apoptotic activity.","method":"Overexpression in 293/MCF7 cells, mutational analysis, NF-κB reporter assays, apoptosis assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, reporter assay, apoptosis readout) replicated across two independent papers (PMID:9989495, PMID:10319863)","pmids":["9989495","10319863"],"is_preprint":false},{"year":1999,"finding":"BCL10 (also called mE10/CIPER/CLAP/c-E10) contains an N-terminal CARD that forms homodimers; the C-terminal region binds pro-caspase-9 and promotes its autoproteolytic activation to induce apoptosis, with CARD-mediated oligomerization being essential for killing activity.","method":"Overexpression in MCF-7 cells, co-immunoprecipitation, mutational analysis, caspase processing assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of caspase-9 activation, mutagenesis, replicated across multiple 1999 papers (PMID:10187815, PMID:10187770, PMID:10364242)","pmids":["10187815","10187770","10364242"],"is_preprint":false},{"year":1999,"finding":"BCL10 CARD domain activates NF-κB through a NIK-dependent pathway upstream of IKKα; the CARD is both necessary and sufficient for NF-κB activation and for homodimerization.","method":"Mutational analysis, dominant-negative NIK/IκBα constructs, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis plus epistasis with dominant-negative constructs, replicated across multiple 1999 papers (PMID:10187770, PMID:10364242)","pmids":["10187770","10364242"],"is_preprint":false},{"year":2001,"finding":"BCL10 is a positive regulator of antigen receptor-induced NF-κB activation in B and T lymphocytes. BCL10-deficient mice show complete absence of antigen receptor-induced NF-κB activation while retaining normal Ca2+ signaling, MAPK, and AP-1 activation, placing BCL10 specifically in the NF-κB branch downstream of antigen receptors.","method":"Bcl10 knockout mice, lymphocyte stimulation assays, NF-κB activation assays, genetic epistasis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined NF-κB-specific phenotype, replicated by multiple labs","pmids":["11163238"],"is_preprint":false},{"year":2001,"finding":"BCL10 and MALT1 form a specific protein complex; BCL10 mediates oligomerization and activation of the MALT1 caspase-like domain, and together they synergistically activate NF-κB through the IKK complex. BCL10 bridges the BIMP1/MALT1 interaction in a ternary complex.","method":"Co-immunoprecipitation, NF-κB reporter assays, dominant-negative mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, reconstitution of ternary complex, replicated across multiple papers (PMID:11262391, PMID:11387339)","pmids":["11262391","11387339"],"is_preprint":false},{"year":2001,"finding":"CARD11/CARMA1 binds BCL10 via CARD-CARD interaction, induces phosphorylation of BCL10, and translocates BCL10 from cytoplasm to perinuclear structures, thereby activating NF-κB. CARD11 and CARD14 both associate specifically with the BCL10 CARD domain.","method":"Co-immunoprecipitation, co-transfection, subcellular localization by immunofluorescence, NF-κB reporter assays","journal":"FEBS letters / The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, localization experiment with functional consequence, replicated across multiple papers (PMID:11356195, PMID:11278692)","pmids":["11356195","11278692"],"is_preprint":false},{"year":2000,"finding":"CARD9 directly interacts with the BCL10 CARD domain (but not other CARD-containing proteins), forms a pre-existing signaling complex with endogenous BCL10, and activates NF-κB as an upstream activator of BCL10.","method":"Mammalian two-hybrid, co-immunoprecipitation of endogenous proteins, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP plus two-hybrid, single lab","pmids":["11053425"],"is_preprint":false},{"year":2003,"finding":"BCL10 activates NF-κB by targeting NEMO/IKKγ for K63-linked polyubiquitination, requiring MALT1 (paracaspase) and UBC13 as a ubiquitin-conjugating enzyme. A NEMO mutant unable to be ubiquitinated blocks BCL10-induced NF-κB activation.","method":"siRNA knockdown, ubiquitination assays, NEMO ubiquitination-site mutants, NF-κB reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination reconstitution, mutagenesis of NEMO ubiquitination sites, multiple orthogonal methods","pmids":["14695475"],"is_preprint":false},{"year":2004,"finding":"TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation downstream of BCL10 and MALT1. Only oligomeric (high-molecular-weight) forms of BCL10 and MALT1 can activate IKK in vitro. MALT1 oligomers bind TRAF6, induce TRAF6 oligomerization, and activate TRAF6 ligase activity to polyubiquitinate NEMO.","method":"In vitro reconstitution with purified proteins, RNAi silencing, IKK activation assays, gel filtration to isolate oligomers","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — full in vitro reconstitution with purified components plus RNAi validation, multiple orthogonal methods","pmids":["15125833"],"is_preprint":false},{"year":2004,"finding":"CARMA1 recruits BCL10 and IKKβ into lipid rafts of the immunological synapse in a CD3/CD28-dependent manner; CARMA1 membrane association is required for this recruitment, and a CARMA1 mutant unable to associate with BCL10 fails to rescue NF-κB activation.","method":"Lipid raft fractionation, immunological synapse imaging, CARMA1-deficient T cell complementation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular fractionation with functional consequence, genetic rescue experiments in CARMA1-deficient cells","pmids":["14673152"],"is_preprint":false},{"year":2004,"finding":"BCL10 degradation following TCR/PKC stimulation occurs via the lysosomal pathway (not proteasome), requires an intact CARD domain, and is promoted by HECT-domain ubiquitin ligases NEDD4 and Itch, which ubiquitinate BCL10. This degradation selectively terminates IKK/NF-κB signaling.","method":"Proteasome inhibitor treatment, lysosome fractionation, ubiquitin ligase overexpression/knockdown, NF-κB activity assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and biochemical fractionation, single lab","pmids":["15082780"],"is_preprint":false},{"year":2006,"finding":"IKKβ plays a dual role at the CBM complex: it is required for initial CBM complex formation, but upon engagement IKKβ phosphorylates BCL10 at its C-terminus, disrupting BCL10/MALT1 association and BCL10-mediated IKKγ ubiquitination, thereby providing negative feedback. Mutation of IKKβ phosphorylation sites on BCL10 enhances NF-κB target gene expression.","method":"Co-immunoprecipitation, IKKβ phosphorylation site mutagenesis, primary T cell NF-κB reporter assays, IL-2/TNFα measurement","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis validated in primary T cells, multiple orthogonal methods","pmids":["16818229"],"is_preprint":false},{"year":2006,"finding":"cIAP2 functions as an E3 ubiquitin ligase for BCL10, targeting it for degradation and thereby inhibiting antigen receptor-mediated cytokine production. The cIAP2-MALT1 fusion protein lacks E3 activity, leading to BCL10 stabilization in MALT lymphomas.","method":"In vitro ubiquitination assay, co-immunoprecipitation, BCL10 protein stability assays, cytokine production assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E3 activity toward BCL10, mutagenesis, single lab","pmids":["16395405"],"is_preprint":false},{"year":2006,"finding":"BCL10 and MALT1 are essential for FcεRI-mediated NF-κB activation and pro-inflammatory cytokine production in mast cells, but are dispensable for degranulation and leukotriene secretion, demonstrating that BCL10 selectively controls the NF-κB arm downstream of FcεRI.","method":"Bcl10−/− and Malt1−/− mice, mast cell stimulation, cytokine ELISA, degranulation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts with defined parallel functional readouts dissecting pathway branches","pmids":["16432253"],"is_preprint":false},{"year":2006,"finding":"CARMA3/BCL10/MALT1 form a signalosome that mediates angiotensin II receptor (GPCR)-dependent NF-κB activation in hepatocytes and vascular cells, acting through IKKγ ubiquitination. BCL10-deficient mice show defective hepatic cytokine production after Ang II treatment.","method":"Dominant-negative mutants, RNAi, gene targeting (Bcl10−/− mice), IKKγ ubiquitination assay, cytokine ELISA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo plus RNAi plus dominant-negative, multiple orthogonal approaches","pmids":["17101977"],"is_preprint":false},{"year":2006,"finding":"BCL10 and MALT1 are required for lysophosphatidic acid (LPA)-induced NF-κB activation and IL-6 production downstream of G protein-coupled receptors in non-immune cells, cooperating with PKC. BCL10/MALT1 are dispensable for LPA-activated JNK, p38, ERK, and Akt.","method":"Bcl10−/− and Malt1−/− mouse embryonic fibroblasts, IκBα degradation assays, IL-6 ELISA, kinase pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout cells with parallel pathway dissection, multiple functional readouts","pmids":["17095601"],"is_preprint":false},{"year":2007,"finding":"BCL10 is phosphorylated at Ser138 by CaMKII following TCR stimulation; phosphorylation at this residue by CaMKII is required for CaMKII's ability to regulate interactions within the Carma1-BCL10-MALT1 complex and for signal-induced ubiquitinations of BCL10 and IKKγ.","method":"In vitro kinase assay (CaMKII + BCL10), CaMKII inhibitor KN93, CaMKII siRNA, S138A mutagenesis, NF-κB reporter assays","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro phosphorylation assay with mutagenesis, pharmacological and RNAi validation, single lab","pmids":["17052756","21513986"],"is_preprint":false},{"year":2006,"finding":"Phosphorylation of BCL10 at Ser138 negatively regulates NF-κB activation: the S138A mutation impairs TCR-induced ubiquitination and subsequent degradation of BCL10, prolonging NF-κB activation and enhancing IL-2 production.","method":"Phosphorylation site mutagenesis (S138A), ubiquitination assays, NF-κB reporter assays, IL-2 ELISA","journal":"Journal of immunology / Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of phosphorylation site with mechanistic downstream readouts, replicated across two papers (PMID:17371994, PMID:17502353)","pmids":["17371994","17502353"],"is_preprint":false},{"year":2007,"finding":"IKK complex phosphorylates BCL10 after TCR stimulation and causes its proteolysis via the β-TrCP ubiquitin ligase/proteasome pathway, providing a negative feedback loop. BCL10 mutants at IKK phosphorylation sites are resistant to degradation, accumulate in the nucleus, and increase IL-2 production.","method":"In vitro IKK kinase assay, proteasome inhibitors, β-TrCP overexpression, phosphorylation-site mutagenesis, IL-2 measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay plus mutagenesis plus in-cell validation, single lab","pmids":["17213322"],"is_preprint":false},{"year":2007,"finding":"BCL10 (but not CARMA1) controls TCR-induced and FcγR-induced actin polymerization independently of NF-κB activation. Phosphorylation-deficient S138A BCL10 specifically inhibits TCR-induced actin polymerization without affecting NF-κB. BCL10 silencing impairs phagocytosis in monocytes.","method":"BCL10 siRNA, S138A mutagenesis, F-actin staining, phagocytosis assays, NF-κB reporter assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus phospho-site mutagenesis dissecting NF-κB vs. actin functions, single lab","pmids":["17371994"],"is_preprint":false},{"year":2008,"finding":"K63-linked polyubiquitination of BCL10 at residues K31 and K63 is required for NEMO/IKKγ binding and NF-κB activation following TCR stimulation. Mutation of these ubiquitination sites prevents NEMO recruitment without affecting CBM complex assembly.","method":"K63-ubiquitin linkage-specific assays, BCL10 ubiquitination site mutagenesis (K31R, K63R), NEMO binding assay, NF-κB reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis with mechanistic dissection of CBM assembly vs. NEMO recruitment, rigorous controls","pmids":["18287044"],"is_preprint":false},{"year":2008,"finding":"Bcl10-MALT1 interaction involves multiple protein domains: a 13-aa region C-terminal to the Bcl10 CARD interacts with MALT1 Ig-like domains, and additionally the MALT1 death domain and BCL10 CARD (especially residues D80 and E84 of helix 5) contribute to the interaction. CARD mutations that disrupt folding strongly impair BCL10-MALT1 interaction.","method":"Co-immunoprecipitation, FRET in T cells, point mutagenesis of conserved BCL10 CARD residues, molecular modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP plus mutagenesis, single lab","pmids":["18806265"],"is_preprint":false},{"year":2008,"finding":"CARD11 recruits multiple signaling cofactors (BCL10, TRAF6, TAK1, IKKγ, caspase-8) through its CARD and coiled-coil domains in a signal-inducible manner; BCL10 and MALT1 are independently recruited to CARD11 and can associate with certain cofactors independently of one another.","method":"RNAi rescue assays, co-immunoprecipitation in BCL10- and MALT1-deficient cells, NF-κB reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue plus Co-IP in deficient cell lines, single lab","pmids":["18625728"],"is_preprint":false},{"year":2003,"finding":"RIP2 kinase associates with BCL10 following TCR engagement and phosphorylates BCL10. RIP2-deficient T cells show defective BCL10 phosphorylation and NF-κB activation; kinase-dead RIP2 cannot rescue NF-κB activation in Rip2−/− fibroblasts.","method":"Co-immunoprecipitation, Rip2−/− mice, kinase-dead mutant complementation, NF-κB assays, BCL10 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus kinase-dead rescue plus Co-IP, single lab","pmids":["14638696"],"is_preprint":false},{"year":2004,"finding":"BCL10 interacts with Pellino2 downstream of TLR4 in response to LPS; BCL10 is recruited to TLR4 signaling complexes, and this recruitment is negatively regulated by SOCS3. BCL10-deficient macrophages show defective LPS-induced NF-κB activation while AP-1 and Elk-1 signaling remain intact.","method":"Co-immunoprecipitation, BCL10-deficient macrophage cell line, SOCS3 overexpression, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in TLR4 complex plus genetic deficiency cell line, single lab","pmids":["15213237"],"is_preprint":false},{"year":2006,"finding":"BCL10 and MALT1 are required for NK cell-mediated NF-κB and JNK/p38 MAPK activation downstream of ITAM-coupled receptors (NK1.1, Ly49D, Ly49H, NKG2D), and depend on CARMA1 (not CARD9). These cascades selectively control cytokine/chemokine production but not cytotoxicity.","method":"Bcl10−/−, Malt1−/−, Carma1−/−, Card9−/− primary NK cells, cytokine production assays, cytotoxicity assays, NF-κB reporter assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — four independent genetic knockouts with parallel functional dissection of cytokine vs. cytotoxicity branches","pmids":["18192506"],"is_preprint":false},{"year":2006,"finding":"CARMA1-BCL10 complex selectively regulates JNK2 (not JNK1) after TCR stimulation: BCL10 is inducibly associated with JNK2 and acts as a JIP-like scaffold to assemble JNK2, MKK7, and TAK1 kinases, regulating c-Jun protein levels.","method":"Co-immunoprecipitation, CARMA1/BCL10 knockout cells, JNK isoform-specific analysis, kinase assays","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic evidence plus Co-IP of endogenous complex, single lab","pmids":["17189706"],"is_preprint":false},{"year":2006,"finding":"BCL10 interacts with IRAK-1 upstream in the TLR4 pathway; upon BCL10 dissociation from IRAK-1, BCL10 translocates to cytosol with TRAF6 and TAK1 via a direct BCL10-Pellino2 interaction. BCL10 oligomerization is a prerequisite for its function in LPS-induced NF-κB signaling.","method":"Co-immunoprecipitation, siRNA against MALT1, subcellular fractionation, NF-κB activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus fractionation plus RNAi, single lab","pmids":["16831874"],"is_preprint":false},{"year":2011,"finding":"Calcineurin (Ca2+-dependent phosphatase) directly dephosphorylates BCL10 in vivo and in vitro and interacts with the CBM complex; calcineurin activity positively regulates CBM complex formation and TCR-induced NF-κB. BCL10 is hyperphosphorylated when calcineurin is inhibited by CsA or FK506.","method":"In vitro phosphatase assay (calcineurin + BCL10), calcineurin A siRNA, CsA/FK506 treatment, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro dephosphorylation assay, pharmacological and siRNA validation, single lab","pmids":["21199863"],"is_preprint":false},{"year":2011,"finding":"E3 ubiquitin ligase MIB2 directly interacts with BCL10, promotes autoubiquitination and ubiquitination of IKKγ/NEMO, and recruits/activates TAK1 as part of the activated BCL10 complex. MIB2 knockdown inhibits BCL10-dependent NF-κB activation.","method":"Proteomic identification, in vitro pulldown, overexpression NF-κB assays, MIB2 knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pulldown plus overexpression/knockdown, single lab","pmids":["21896478"],"is_preprint":false},{"year":2012,"finding":"BCL10 has an NF-κB-independent role in actin and membrane remodeling downstream of FcγR in macrophages. BCL10 depletion impairs Rac1 and PI3K activation and leads to abortive phagocytic cups. BCL10 forms a complex with clathrin adaptors AP1 and EpsinR and is required to deliver the OCRL phosphatase (which regulates PI(4,5)P2 and F-actin) to the phagocytic cup.","method":"BCL10 depletion by siRNA, phagocytosis assays, Rac1/PI3K activation assays, co-immunoprecipitation with AP1/EpsinR, PI(4,5)P2 imaging","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue with F-actin depolymerizing drugs, multiple readouts, single lab","pmids":["23153494"],"is_preprint":false},{"year":2012,"finding":"TCR engagement triggers selective autophagy of BCL10 in effector (but not naive) T cells, requiring K63-polyubiquitination of BCL10 and subsequent association with the autophagy adaptor p62. p62 binding is required for both BCL10 signaling to NF-κB and gradual BCL10 degradation; blockade of BCL10 autophagy enhances NF-κB activation.","method":"Autophagy inhibition, ubiquitin linkage-specific assays, p62 knockout/knockdown, BCL10 degradation assays, NF-κB activation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ubiquitination assay, genetic p62 depletion, autophagy blockade) with clear mechanistic model","pmids":["22658522"],"is_preprint":false},{"year":2013,"finding":"The reconstituted CBM signalosome forms a helical filamentous assembly: CARMA1 nucleates BCL10 filament formation through CARD-CARD interactions in a cooperative, threshold-sensitive manner; MALT1 binds BCL10 filaments and is activated; structure of the BCL10 CARD filament was determined by crystallography, NMR, and EM. Structure-guided mutagenesis confirmed interfaces required for BCL10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells.","method":"Cryo-EM, crystallography, NMR, in vitro reconstitution of CBM filament, structure-guided mutagenesis, NF-κB reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic structure plus reconstitution plus mutagenesis in cells, multiple orthogonal methods in single study","pmids":["24074955"],"is_preprint":false},{"year":2014,"finding":"BCL10 polymerizes in a unidirectional manner as shown by time-lapse confocal imaging; cryo-EM structure of the BCL10 CARD filament at 4.0 Å resolution redefines CARD-CARD interfaces. CARMA1 serves as a hub forming star-shaped filamentous BCL10 networks and decreases BCL10 polymerization lag time. MALT1 immediately dimerizes on BCL10 filaments, and TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies.","method":"Cryo-EM at 4.0 Å, time-lapse confocal imaging, EM of MALT1 and TRAF6 decoration of filaments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic structure plus live-cell imaging plus EM of higher-order assemblies, multiple orthogonal methods","pmids":["29382759"],"is_preprint":false},{"year":2014,"finding":"A cytosolic p62-BCL10-MALT1-IKK signalosome forms in effector T cells upon TCR stimulation; the active IKK complex is a component of this signalosome; phosphorylated IκBα and NF-κB are transiently recruited before nuclear NF-κB translocation. p62-dependent clustering is required for NF-κB activation in effector T cells.","method":"Co-immunoprecipitation, p62-deficient T cells, confocal imaging of signalosome clusters, IKK activity assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic p62 knockout plus biochemical Co-IP of endogenous complex, single lab","pmids":["24825920"],"is_preprint":false},{"year":2014,"finding":"BCL10 is NOT required for TCR/CD28-induced mTOR activation in T cells; this distinguishes the BCL10 requirement for NF-κB from a CARMA1/MALT1-dependent but BCL10-independent pathway to mTOR signaling.","method":"BCL10-deficient T cells, mTOR pathway activation assays, metabolic flux assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined negative result for mTOR, single lab; negative finding mechanistically informative","pmids":["24917592"],"is_preprint":false},{"year":2005,"finding":"MALT1 contains nuclear export signals (NES) and controls the cytoplasmic localization of BCL10; MALT1 is involved in nuclear export of BCL10, shuttling between nucleus and cytoplasm. Leptomycin B (NES inhibitor) retains MALT1 and BCL10 in the nucleus.","method":"Deletion mutagenesis of MALT1 NES, leptomycin B treatment, subcellular fractionation and imaging","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and mutagenesis-based localization experiments, single lab","pmids":["16123224"],"is_preprint":false},{"year":2005,"finding":"BCL10 undergoes nuclear translocation in response to TNFα: Akt1 phosphorylates BCL10 at Ser218 and Ser231, and phosphorylated BCL10 then complexes with Bcl3 to enter the nucleus. An NF-κB-binding site in the BCL10 5'-UTR drives NF-κB-dependent BCL10 upregulation.","method":"Chromatin immunoprecipitation, EMSA, Akt1 kinase assay, Bcl3 co-immunoprecipitation, Akt1 inhibitor, Bcl3 depletion","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro Akt1 phosphorylation of BCL10, Co-IP with Bcl3, ChIP, inhibitor validation, single lab","pmids":["16280327"],"is_preprint":false},{"year":2010,"finding":"LPS activates the non-canonical NF-κB pathway (RelB/p52) in colonic epithelial cells through BCL10; phosphorylation of BCL10 Ser138 is required for NIK phosphorylation and subsequent RelB/p52 nuclear translocation. Mutation of Ser138 or Ser218 reduces both canonical and non-canonical NF-κB activation.","method":"BCL10 siRNA, BCL10 phosphorylation-site mutagenesis (S138G, S218G), nuclear RelB/p52 assays, phospho-NIK assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of specific phosphorylation sites with multiple NF-κB pathway readouts, single lab","pmids":["20466000"],"is_preprint":false},{"year":2009,"finding":"COP9 signalosome subunit CSN5 interacts with MALT1 and CARMA1; TCR activation recruits CSN to the CBM complex. The CSN is required for maintaining BCL10 stability in response to T cell activation and for TCR-induced IKK activation.","method":"Co-immunoprecipitation, CSN5 siRNA knockdown, BCL10 stability assays, IKK activation assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of endogenous complex plus siRNA, single lab","pmids":["19444310"],"is_preprint":false},{"year":2016,"finding":"BCL10 undergoes TCR-induced conjugation with linearly-linked (M1) polyubiquitin chains (Lin(Ub)n-BCL10) at lysines K17, K31, and K63; linear ubiquitination requires CARD11, MALT1, and the HOIP subunit of LUBAC. Lin(Ub)n-BCL10 is required for NEMO/IKK recruitment. CARD11 co-recruits BCL10 with HOIP to bring substrate to enzyme.","method":"Linkage-specific ubiquitin assays, BCL10 lysine mutagenesis, HOIP/LUBAC knockdown, CARD11 co-IP experiments, NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — linear ubiquitin-specific assays, site-directed mutagenesis at three lysines, genetic depletion, mechanistic model with substrate-enzyme co-recruitment","pmids":["27777308"],"is_preprint":false},{"year":2018,"finding":"GSK3β regulates CBM complex formation through site-specific phosphorylation of BCL10; GSK3β inhibition reduces BCL10 phosphorylation, impairs CBM assembly, and consequently reduces MALT1 protease-dependent cleavage of substrates (BCL10, CYLD, RelB), IκBα degradation, and NF-κB activity.","method":"GSK3β pharmacological inhibitors (SB216763, SB415286), GSK3β RNAi, BCL10 phosphorylation assays, MALT1 substrate cleavage assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus RNAi plus multiple downstream readouts, single lab","pmids":["29358699"],"is_preprint":false},{"year":2019,"finding":"BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in regulatory T cells and controls their suppressive function; BCL10-dependent MALT1 protease activity is specifically required for Treg suppressive function. Acute BCL10 deletion in mature Tregs impairs suppression and causes lethal autoimmunity.","method":"Conditional BCL10 knockout in Tregs (Bcl10fl/fl Foxp3cre), Treg suppression assays, Rag1−/− colitis transfer, gene expression profiling, MALT1 inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout with defined suppression phenotype plus MALT1 inhibitor validation, multiple orthogonal readouts","pmids":["31138793"],"is_preprint":false},{"year":2022,"finding":"BCL10 mutations in ABC-DLBCL fall into two biochemically distinct classes: (1) CARD missense mutations enhance BCL10 filament formation via glutamine network structures that stabilize filaments; (2) C-terminal truncating mutations abrogate a MALT1 inhibitory motif, trapping MALT1 in activated filament-bound state. Both classes confer BTK inhibitor resistance, while truncating (not CARD) mutants are hypersensitive to MALT1 inhibitors.","method":"Structural analysis, BCL10 polymerization assays, MALT1 activity assays, BTK inhibitor/MALT1 inhibitor drug sensitivity testing in primary lymphoma and cell lines","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-function analysis with biochemical polymerization assays, mutagenesis, and pharmacological validation across multiple mutation classes","pmids":["35658124"],"is_preprint":false}],"current_model":"BCL10 is a CARD-domain adaptor protein that, upon antigen receptor or GPCR stimulation, is recruited by CARMA/CARD scaffold proteins (CARMA1 in lymphocytes, CARMA3 in non-immune cells) to nucleate cooperative BCL10 CARD filament formation, which scaffolds MALT1 dimerization and TRAF6 recruitment, leading to K63-linked and linear polyubiquitination of BCL10 and NEMO/IKKγ (mediated by UBC13/LUBAC/HOIP), TAK1 activation, and canonical IKK/NF-κB activation; BCL10 activity is tightly regulated by phosphorylation (by CaMKII, RIP2, IKKβ, and Akt1), ubiquitination (by NEDD4/Itch, cIAP2, MIB2), and degradation via lysosomal/autophagic (p62-dependent) and proteasomal (β-TrCP-dependent) pathways, with calcineurin providing positive feedback through BCL10 dephosphorylation; independently of NF-κB, BCL10 controls actin polymerization and phagocytic cup closure via a complex with AP1/EpsinR and the OCRL phosphatase."},"narrative":{"mechanistic_narrative":"BCL10 is a CARD-domain adaptor protein that serves as the central signal-amplifying scaffold linking antigen and G protein-coupled receptors to canonical NF-κB activation [PMID:11163238, PMID:17101977]. Its N-terminal CARD mediates homo-oligomerization, an activity essential for both NF-κB activation and, in overexpression settings, caspase-9-dependent apoptosis [PMID:9989495, PMID:10319863, PMID:10187815, PMID:10187770, PMID:10364242]. Upon receptor engagement, CARMA/CARD scaffolds (CARMA1 in lymphocytes, CARMA3 in non-immune cells, CARD9 in myeloid contexts) bind the BCL10 CARD and nucleate cooperative, unidirectional BCL10 CARD filament assembly, which recruits BCL10 to membrane lipid rafts at the immunological synapse and templates MALT1 dimerization and TRAF6 decoration into a higher-order CBM signalosome [PMID:11356195, PMID:11278692, PMID:11053425, PMID:14673152, PMID:24074955, PMID:29382759]. Within this assembly BCL10 oligomers, together with MALT1 paracaspase activity, drive TRAF6/UBC13- and LUBAC/HOIP-dependent K63-linked and linear (M1) polyubiquitination of BCL10 itself (at K17/K31/K63) and of NEMO/IKKγ, recruiting and activating the IKK complex via TAK1 to trigger IκBα degradation and NF-κB nuclear translocation [PMID:14695475, PMID:15125833, PMID:18287044, PMID:27777308]. BCL10 signaling is selective for the NF-κB branch, being dispensable for Ca2+ flux, MAPK/AP-1, and mTOR activation downstream of these receptors [PMID:11163238, PMID:17095601, PMID:24917592]. Signal output is tightly bounded by a phosphorylation and degradation network: CaMKII (Ser138), RIP2, IKKβ, and Akt1 phosphorylate BCL10 with both activating and feedback-terminating consequences, calcineurin dephosphorylates BCL10 to sustain CBM assembly, and BCL10 is degraded through NEDD4/Itch- and cIAP2-driven lysosomal, p62-dependent autophagic, and β-TrCP-dependent proteasomal routes [PMID:15082780, PMID:16818229, PMID:16395405, PMID:17052756, PMID:21513986, PMID:17371994, PMID:17502353, PMID:17213322, PMID:21199863, PMID:22658522]. BCL10 also performs an NF-κB-independent function in actin and membrane remodeling, controlling Fcγ/TCR-induced actin polymerization and phagocytic cup closure through a complex with the clathrin adaptors AP1/EpsinR that delivers the OCRL phosphatase to the phagocytic cup [PMID:17371994, PMID:23153494]. Activating CARD missense and C-terminal truncating BCL10 mutations drive constitutive CBM signaling in ABC-DLBCL and confer distinct therapeutic vulnerabilities [PMID:35658124].","teleology":[{"year":1999,"claim":"Established the founding molecular activity of BCL10: that its N-terminal CARD drives self-oligomerization, which is required both to activate NF-κB and to engage caspase-9-dependent apoptosis, defining BCL10 as a bifunctional CARD adaptor.","evidence":"Overexpression, mutational analysis, NF-κB reporter and caspase processing assays in 293/MCF-7 cells","pmids":["9989495","10319863","10187815","10187770","10364242"],"confidence":"High","gaps":["Performed in overexpression systems; physiological relevance of the apoptotic arm not established","Did not identify upstream receptors or scaffolds engaging BCL10"]},{"year":1999,"claim":"Placed BCL10 in the NF-κB cascade upstream of IKKα via a NIK-dependent route, showing the CARD is both necessary and sufficient for signaling.","evidence":"Dominant-negative NIK/IκBα constructs and NF-κB reporter assays","pmids":["10187770","10364242"],"confidence":"High","gaps":["Did not define the receptor input or direct downstream ubiquitination targets","NIK-dependence later refined to canonical IKK activation"]},{"year":2001,"claim":"Genetic knockout demonstrated that BCL10 is specifically required for antigen-receptor-induced NF-κB in lymphocytes while sparing Ca2+, MAPK, and AP-1 signaling, fixing BCL10 to the NF-κB branch in vivo.","evidence":"Bcl10-deficient mice with lymphocyte stimulation and pathway-specific NF-κB assays","pmids":["11163238"],"confidence":"High","gaps":["Did not resolve the molecular bridge between the receptor and BCL10","Mechanism of NF-κB-branch selectivity unexplained"]},{"year":2001,"claim":"Defined the core CBM assembly by showing BCL10 bridges CARMA-type scaffolds to MALT1, oligomerizing and activating the MALT1 caspase-like domain for synergistic IKK-dependent NF-κB activation.","evidence":"Co-immunoprecipitation, ternary complex reconstitution, dominant-negative NF-κB reporter assays; CARMA1/CARD11 CARD-CARD binding and BCL10 translocation imaging","pmids":["11262391","11387339","11356195","11278692"],"confidence":"High","gaps":["Did not show how MALT1 oligomerization leads to IKK activation biochemically","Structural basis of CARD-CARD nucleation unknown"]},{"year":2003,"claim":"Identified the biochemical output of the CBM complex: BCL10/MALT1 direct K63-linked polyubiquitination of NEMO/IKKγ via UBC13, defining ubiquitin signaling as the link to IKK activation.","evidence":"siRNA knockdown, in vitro ubiquitination, NEMO ubiquitination-site mutants, NF-κB reporter assays; RIP2 association/phosphorylation of BCL10 from knockout mice","pmids":["14695475","14638696"],"confidence":"High","gaps":["E3 ligase responsible not yet pinned to TRAF6","Order of BCL10 vs NEMO ubiquitination unresolved"]},{"year":2004,"claim":"Reconstituted the activation mechanism with purified components, showing oligomeric BCL10/MALT1 binds and activates TRAF6 ligase, which polyubiquitinates NEMO and engages TAK1 to activate IKK, and localized assembly to immunological-synapse lipid rafts.","evidence":"In vitro reconstitution with purified proteins, gel filtration of oligomers, RNAi; lipid raft fractionation and CARMA1-deficient T cell complementation","pmids":["15125833","14673152"],"confidence":"High","gaps":["Did not visualize the higher-order architecture of the active complex","How oligomerization threshold is set in cells unknown"]},{"year":2004,"claim":"Revealed signal termination logic by showing TCR-induced lysosomal degradation of BCL10 driven by HECT E3 ligases NEDD4/Itch, selectively shutting down NF-κB.","evidence":"Proteasome inhibitors, lysosome fractionation, E3 ligase overexpression/knockdown, NF-κB assays","pmids":["15082780"],"confidence":"Medium","gaps":["Single lab; relative contribution of lysosomal vs other degradation routes unquantified","Ubiquitin linkage type targeting BCL10 to lysosome not defined"]},{"year":2004,"claim":"Extended BCL10 function beyond antigen receptors to innate TLR4 signaling, showing recruitment to TLR4 complexes and a requirement for LPS-induced NF-κB, with SOCS3 as a negative regulator.","evidence":"Co-IP, BCL10-deficient macrophage line, SOCS3 overexpression, NF-κB reporter assays; IRAK-1/Pellino2 interactions and fractionation","pmids":["15213237","16831874"],"confidence":"Medium","gaps":["TLR4-to-BCL10 connection less defined than antigen-receptor axis","Single-lab Co-IP and fractionation without reconstitution"]},{"year":2005,"claim":"Uncovered nucleocytoplasmic regulation of BCL10: MALT1 NES-driven export controls BCL10 cytoplasmic localization, while Akt1 phosphorylation (Ser218/Ser231) and Bcl3 binding drive TNFα-induced BCL10 nuclear entry, with NF-κB autoregulating BCL10 transcription.","evidence":"MALT1 NES mutagenesis and leptomycin B; Akt1 kinase assay, Bcl3 Co-IP, ChIP/EMSA, inhibitor validation","pmids":["16123224","16280327"],"confidence":"Medium","gaps":["Functional role of nuclear BCL10 not fully defined","Single-lab studies for each localization branch"]},{"year":2006,"claim":"Generalized BCL10 to GPCR signaling via CARMA3-BCL10-MALT1 signalosomes (angiotensin II, LPA) and to multiple immune effector contexts (mast cells, NK cells), each selectively controlling the NF-κB/cytokine arm while sparing other outputs.","evidence":"Bcl10-/- mice and MEFs, dominant-negative/RNAi, IKKγ ubiquitination and cytokine assays, parallel pathway dissection in mast and NK cells","pmids":["17101977","17095601","16432253","18192506"],"confidence":"High","gaps":["Tissue-specific scaffold partners for each receptor not all mapped","Mechanism of NF-κB-branch selectivity remained unexplained"]},{"year":2006,"claim":"Defined a multi-kinase phosphoregulatory network on BCL10 — CaMKII (Ser138) priming ubiquitination, IKKβ and the IKK complex driving negative-feedback disassembly and β-TrCP/proteasomal degradation — quantitatively tuning NF-κB output.","evidence":"In vitro kinase assays, phospho-site mutagenesis (S138A, IKK sites), ubiquitination/degradation and IL-2 assays in primary T cells","pmids":["16818229","17052756","21513986","17371994","17502353","17213322"],"confidence":"High","gaps":["Temporal coordination of competing kinases not fully resolved","Some phospho-site assignments from single labs"]},{"year":2006,"claim":"Showed BCL10 also scaffolds JNK2 signaling and identified cIAP2 as an E3 ligase degrading BCL10, with loss of this activity in the cIAP2-MALT1 lymphoma fusion stabilizing BCL10.","evidence":"Endogenous Co-IP and JNK isoform-specific kinase assays; in vitro ubiquitination, stability and cytokine assays","pmids":["17189706","16395405"],"confidence":"Medium","gaps":["JNK2 scaffolding role from single lab","Physiological substrate scope of cIAP2 toward BCL10 not generalized"]},{"year":2007,"claim":"Separated BCL10's NF-κB function from a distinct, phosphorylation-dependent role in actin polymerization and phagocytosis, showing S138A selectively blocks actin remodeling without affecting NF-κB.","evidence":"BCL10 siRNA, S138A mutagenesis, F-actin staining, phagocytosis and NF-κB reporter assays","pmids":["17371994"],"confidence":"Medium","gaps":["Effector machinery linking BCL10 to actin not yet identified","Single-lab knockdown study"]},{"year":2008,"claim":"Resolved the ubiquitin code on BCL10 by showing K63-linked ubiquitination at K31/K63 specifically mediates NEMO recruitment downstream of CBM assembly, separating complex formation from IKK recruitment; refined the BCL10 CARD-MALT1 interaction interfaces; and mapped CARD11 cofactor recruitment.","evidence":"Linkage-specific ubiquitin assays, lysine mutagenesis, NEMO-binding assays; FRET, Co-IP, point mutagenesis and modeling; RNAi rescue in deficient cells","pmids":["18287044","18806265","18625728"],"confidence":"High","gaps":["E3 ligase placing these chains on BCL10 not definitively assigned","Interaction-mapping studies single-lab"]},{"year":2011,"claim":"Established positive-feedback dephosphorylation by calcineurin sustaining CBM assembly, and identified MIB2 as an additional BCL10-interacting E3 promoting NEMO ubiquitination and TAK1 activation.","evidence":"In vitro phosphatase assay, calcineurin RNAi and CsA/FK506; proteomic identification, pulldown, knockdown NF-κB assays","pmids":["21199863","21896478"],"confidence":"Medium","gaps":["Both single-lab; integration with the IKKβ/β-TrCP negative arms not modeled","Substrate residues dephosphorylated by calcineurin not mapped"]},{"year":2012,"claim":"Mechanistically defined the NF-κB-independent membrane-remodeling role, showing BCL10 partners with AP1/EpsinV clathrin adaptors to deliver OCRL phosphatase and drive Rac1/PI3K-dependent phagocytic cup closure; and revealed selective autophagy as a degradation/signaling node requiring K63-ubiquitin and p62.","evidence":"siRNA depletion, phagocytosis/Rac1/PI3K assays, AP1/EpsinR Co-IP, PI(4,5)P2 imaging; autophagy inhibition, p62 knockout, BCL10 degradation/NF-κB assays","pmids":["23153494","22658522"],"confidence":"Medium","gaps":["AP1/EpsinR-OCRL pathway from single lab","How phosphorylation gates the choice between NF-κB and actin functions unresolved"]},{"year":2013,"claim":"Provided the structural mechanism: CARMA1 nucleates cooperative, threshold-sensitive, unidirectional BCL10 CARD filament formation that templates MALT1 dimerization/activation and TRAF6 decoration into higher-order CBM assemblies.","evidence":"Cryo-EM, crystallography, NMR, in vitro filament reconstitution, structure-guided mutagenesis with NF-κB readouts; live-cell time-lapse imaging of polymerization","pmids":["24074955","29382759"],"confidence":"High","gaps":["How ubiquitination machinery docks onto the filament structurally not resolved","In vivo filament dynamics in primary cells not quantified"]},{"year":2014,"claim":"Defined effector-T-cell-specific signalosome wiring (p62-BCL10-MALT1-IKK clustering) and sharpened the functional boundary of BCL10 by showing it is dispensable for CARMA1/MALT1-dependent mTOR activation.","evidence":"Co-IP, p62-deficient T cells, confocal imaging, IKK assays; BCL10-deficient T cell mTOR/metabolic assays","pmids":["24825920","24917592"],"confidence":"Medium","gaps":["Both single-lab","Molecular basis distinguishing BCL10-dependent NF-κB from BCL10-independent mTOR branch unresolved"]},{"year":2016,"claim":"Identified linear (M1) ubiquitination of BCL10 at K17/K31/K63 by LUBAC/HOIP, co-recruited with substrate by CARD11, as a required step for NEMO/IKK recruitment, adding a second ubiquitin chain type to BCL10 signaling.","evidence":"Linkage-specific ubiquitin assays, lysine mutagenesis, HOIP/LUBAC knockdown, CARD11 Co-IP, NF-κB reporter assays","pmids":["27777308"],"confidence":"High","gaps":["Interplay between K63 and M1 chains on the same lysines not deconvolved","Single-lab study"]},{"year":2018,"claim":"Added GSK3β as an upstream kinase whose site-specific phosphorylation of BCL10 promotes CBM assembly and downstream MALT1 protease activity.","evidence":"GSK3β inhibitors and RNAi, BCL10 phosphorylation and MALT1 substrate-cleavage assays","pmids":["29358699"],"confidence":"Medium","gaps":["Phosphorylation sites not precisely mapped","Single-lab, largely pharmacological"]},{"year":2019,"claim":"Established the physiological importance of CBM/MALT1 protease activity for regulatory T cell suppressive function, showing acute BCL10 loss in mature Tregs causes lethal autoimmunity.","evidence":"Conditional Bcl10 knockout in Tregs, suppression and colitis-transfer assays, MALT1 inhibitor validation","pmids":["31138793"],"confidence":"High","gaps":["BCL10-dependent transcriptional targets governing suppression not fully mapped","Does not address BCL10 in conventional T cell tolerance"]},{"year":2022,"claim":"Connected BCL10 biology to disease by defining two biochemically distinct oncogenic BCL10 mutation classes in ABC-DLBCL — filament-stabilizing CARD missense and MALT1-disinhibiting C-terminal truncations — with divergent BTK- and MALT1-inhibitor sensitivities.","evidence":"Structural analysis, polymerization and MALT1 activity assays, drug-sensitivity testing in primary lymphoma and cell lines","pmids":["35658124"],"confidence":"High","gaps":["Frequency and prognostic impact across patient cohorts not addressed here","Resistance mechanisms beyond these two classes unknown"]},{"year":null,"claim":"How the multiple competing phosphorylation, ubiquitination, dephosphorylation, and degradation inputs are temporally integrated on the BCL10 filament to set NF-κB amplitude and duration, and what structurally distinguishes BCL10's NF-κB scaffolding from its actin/membrane-remodeling function, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model coupling filament dynamics to PTM cycles","Structural basis of the NF-κB-independent AP1/EpsinR/OCRL function undetermined","Direct E3 ligases for each BCL10 ubiquitin chain type not all assigned"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,9,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,8,40]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,27,34]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[36,37]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,13,25,42]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,14,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[43]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[30]}],"complexes":["CBM signalosome (CARMA1/CARD11-BCL10-MALT1)","p62-BCL10-MALT1-IKK signalosome","BCL10-AP1/EpsinR complex"],"partners":["MALT1","CARD11","CARD9","TRAF6","IKBKG","SQSTM1","RIPK2","AKT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95999","full_name":"B-cell lymphoma/leukemia 10","aliases":["B-cell CLL/lymphoma 10","Bcl-10","CARD-containing molecule enhancing NF-kappa-B","CARD-like apoptotic protein","hCLAP","CED-3/ICH-1 prodomain homologous E10-like regulator","CIPER","Cellular homolog of vCARMEN","cCARMEN","Cellular-E10","c-E10","Mammalian CARD-containing adapter molecule E10","mE10"],"length_aa":233,"mass_kda":26.3,"function":"Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation (PubMed:10187770, PubMed:10364242, PubMed:10400625, PubMed:24074955, PubMed:25365219). Acts by channeling adaptive and innate immune signaling downstream of CARD domain-containing proteins CARD9, CARD11 and CARD14 to activate NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:24074955). Recruited by activated CARD domain-containing proteins: homooligomerized CARD domain-containing proteins form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10, subsequent recruitment of MALT1 and formation of a CBM complex (PubMed:24074955). This leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:18287044, PubMed:24074955, PubMed:27777308). Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity (PubMed:26488816). Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR) (PubMed:18264101, PubMed:18287044, PubMed:24074955, PubMed:27777308). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK (PubMed:10187815)","subcellular_location":"Cytoplasm, perinuclear region; Membrane raft","url":"https://www.uniprot.org/uniprotkb/O95999/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BCL10","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BCL10","total_profiled":1310},"omim":[{"mim_id":"617726","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 19; CARD19","url":"https://www.omim.org/entry/617726"},{"mim_id":"616098","title":"IMMUNODEFICIENCY 37; IMD37","url":"https://www.omim.org/entry/616098"},{"mim_id":"614798","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 2; PELI2","url":"https://www.omim.org/entry/614798"},{"mim_id":"608382","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY A, MEMBER 3; DNAJA3","url":"https://www.omim.org/entry/608382"},{"mim_id":"607212","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 9; CARD9","url":"https://www.omim.org/entry/607212"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BCL10"},"hgnc":{"alias_symbol":["CARMEN","CIPER","mE10","c-E10","CLAP"],"prev_symbol":[]},"alphafold":{"accession":"O95999","domains":[{"cath_id":"1.10.533.10","chopping":"9-113","consensus_level":"high","plddt":91.3005,"start":9,"end":113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95999","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95999-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95999-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BCL10","jax_strain_url":"https://www.jax.org/strain/search?query=BCL10"},"sequence":{"accession":"O95999","fasta_url":"https://rest.uniprot.org/uniprotkb/O95999.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95999/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95999"}},"corpus_meta":[{"pmid":"15125833","id":"PMC_15125833","title":"The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.","date":"2004","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15125833","citation_count":587,"is_preprint":false},{"pmid":"9989495","id":"PMC_9989495","title":"Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9989495","citation_count":535,"is_preprint":false},{"pmid":"11163238","id":"PMC_11163238","title":"Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure.","date":"2001","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11163238","citation_count":440,"is_preprint":false},{"pmid":"14695475","id":"PMC_14695475","title":"Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14695475","citation_count":435,"is_preprint":false},{"pmid":"11262391","id":"PMC_11262391","title":"Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11262391","citation_count":349,"is_preprint":false},{"pmid":"10319863","id":"PMC_10319863","title":"Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32).","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10319863","citation_count":311,"is_preprint":false},{"pmid":"11278692","id":"PMC_11278692","title":"CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278692","citation_count":296,"is_preprint":false},{"pmid":"11053425","id":"PMC_11053425","title":"CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11053425","citation_count":202,"is_preprint":false},{"pmid":"20685844","id":"PMC_20685844","title":"Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1.","date":"2010","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/20685844","citation_count":193,"is_preprint":false},{"pmid":"14673152","id":"PMC_14673152","title":"CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14673152","citation_count":179,"is_preprint":false},{"pmid":"33052760","id":"PMC_33052760","title":"Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial.","date":"2020","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33052760","citation_count":173,"is_preprint":false},{"pmid":"22658522","id":"PMC_22658522","title":"Selective autophagy of the adaptor protein Bcl10 modulates T cell receptor activation of NF-κB.","date":"2012","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22658522","citation_count":172,"is_preprint":false},{"pmid":"11356195","id":"PMC_11356195","title":"Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11356195","citation_count":167,"is_preprint":false},{"pmid":"11387339","id":"PMC_11387339","title":"Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappaB induction.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11387339","citation_count":154,"is_preprint":false},{"pmid":"12910267","id":"PMC_12910267","title":"Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells.","date":"2003","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12910267","citation_count":151,"is_preprint":false},{"pmid":"11021819","id":"PMC_11021819","title":"BCL10 expression in normal and neoplastic lymphoid tissue. Nuclear localization in MALT lymphoma.","date":"2000","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11021819","citation_count":150,"is_preprint":false},{"pmid":"24074955","id":"PMC_24074955","title":"Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24074955","citation_count":150,"is_preprint":false},{"pmid":"17101977","id":"PMC_17101977","title":"CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17101977","citation_count":150,"is_preprint":false},{"pmid":"18252714","id":"PMC_18252714","title":"Toll-like receptor 4 mediates induction of the Bcl10-NFkappaB-interleukin-8 inflammatory pathway by carrageenan in human intestinal epithelial cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18252714","citation_count":138,"is_preprint":false},{"pmid":"10187770","id":"PMC_10187770","title":"CIPER, a novel NF kappaB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10187770","citation_count":132,"is_preprint":false},{"pmid":"23194342","id":"PMC_23194342","title":"In planta expression or delivery of potato aphid Macrosiphum euphorbiae effectors Me10 and Me23 enhances aphid fecundity.","date":"2013","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/23194342","citation_count":122,"is_preprint":false},{"pmid":"18287044","id":"PMC_18287044","title":"NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18287044","citation_count":120,"is_preprint":false},{"pmid":"15082780","id":"PMC_15082780","title":"Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15082780","citation_count":119,"is_preprint":false},{"pmid":"25087226","id":"PMC_25087226","title":"The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.","date":"2014","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25087226","citation_count":116,"is_preprint":false},{"pmid":"16818229","id":"PMC_16818229","title":"Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16818229","citation_count":111,"is_preprint":false},{"pmid":"15682443","id":"PMC_15682443","title":"MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression.","date":"2005","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15682443","citation_count":107,"is_preprint":false},{"pmid":"16432253","id":"PMC_16432253","title":"The Bcl10-Malt1 complex segregates Fc epsilon RI-mediated nuclear factor kappa B activation and cytokine production from mast cell degranulation.","date":"2006","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16432253","citation_count":106,"is_preprint":false},{"pmid":"25202022","id":"PMC_25202022","title":"C-type lectin receptor dectin-3 mediates trehalose 6,6'-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent nuclear factor (NF)-κB activation.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25202022","citation_count":103,"is_preprint":false},{"pmid":"10187815","id":"PMC_10187815","title":"mE10, a novel caspase recruitment domain-containing proapoptotic molecule.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10187815","citation_count":102,"is_preprint":false},{"pmid":"24917592","id":"PMC_24917592","title":"T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24917592","citation_count":97,"is_preprint":false},{"pmid":"10364242","id":"PMC_10364242","title":"CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NF-kappaB activation and apoptosis.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10364242","citation_count":94,"is_preprint":false},{"pmid":"15541657","id":"PMC_15541657","title":"The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling.","date":"2004","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15541657","citation_count":92,"is_preprint":false},{"pmid":"18192506","id":"PMC_18192506","title":"Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18192506","citation_count":91,"is_preprint":false},{"pmid":"16395405","id":"PMC_16395405","title":"cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas.","date":"2006","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/16395405","citation_count":89,"is_preprint":false},{"pmid":"29382759","id":"PMC_29382759","title":"Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29382759","citation_count":88,"is_preprint":false},{"pmid":"17189706","id":"PMC_17189706","title":"The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway.","date":"2006","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17189706","citation_count":88,"is_preprint":false},{"pmid":"30283440","id":"PMC_30283440","title":"The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30283440","citation_count":86,"is_preprint":false},{"pmid":"19144384","id":"PMC_19144384","title":"BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome.","date":"2009","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19144384","citation_count":86,"is_preprint":false},{"pmid":"10845924","id":"PMC_10845924","title":"BCL10 gene mutation in lymphoma.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10845924","citation_count":85,"is_preprint":false},{"pmid":"21199863","id":"PMC_21199863","title":"The Ca2+-dependent phosphatase calcineurin controls the formation of the Carma1-Bcl10-Malt1 complex during T cell receptor-induced NF-kappaB activation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21199863","citation_count":85,"is_preprint":false},{"pmid":"17095601","id":"PMC_17095601","title":"Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17095601","citation_count":83,"is_preprint":false},{"pmid":"16831874","id":"PMC_16831874","title":"The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16831874","citation_count":82,"is_preprint":false},{"pmid":"25365219","id":"PMC_25365219","title":"Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25365219","citation_count":80,"is_preprint":false},{"pmid":"14638696","id":"PMC_14638696","title":"Rip2 participates in Bcl10 signaling and T-cell receptor-mediated NF-kappaB activation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14638696","citation_count":78,"is_preprint":false},{"pmid":"31138793","id":"PMC_31138793","title":"Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31138793","citation_count":75,"is_preprint":false},{"pmid":"29259013","id":"PMC_29259013","title":"The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29259013","citation_count":74,"is_preprint":false},{"pmid":"17213322","id":"PMC_17213322","title":"Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17213322","citation_count":74,"is_preprint":false},{"pmid":"26668357","id":"PMC_26668357","title":"Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26668357","citation_count":72,"is_preprint":false},{"pmid":"10400625","id":"PMC_10400625","title":"c-E10 is a caspase-recruiting domain-containing protein that interacts with components of death receptors signaling pathway and activates nuclear factor-kappaB.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10400625","citation_count":69,"is_preprint":false},{"pmid":"21041303","id":"PMC_21041303","title":"Thrombin-dependent NF-{kappa}B activation and monocyte/endothelial adhesion are mediated by the CARMA3·Bcl10·MALT1 signalosome.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21041303","citation_count":69,"is_preprint":false},{"pmid":"27135977","id":"PMC_27135977","title":"Role of the CARMA1/BCL10/MALT1 complex in lymphoid malignancies.","date":"2016","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/27135977","citation_count":66,"is_preprint":false},{"pmid":"23153494","id":"PMC_23153494","title":"The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23153494","citation_count":66,"is_preprint":false},{"pmid":"20605784","id":"PMC_20605784","title":"The CARMA3-Bcl10-MALT1 signalosome promotes angiotensin II-dependent vascular inflammation and atherogenesis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20605784","citation_count":66,"is_preprint":false},{"pmid":"27420898","id":"PMC_27420898","title":"Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome.","date":"2016","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27420898","citation_count":64,"is_preprint":false},{"pmid":"11830492","id":"PMC_11830492","title":"BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11830492","citation_count":61,"is_preprint":false},{"pmid":"19066953","id":"PMC_19066953","title":"The monoclonal anti-BCL10 antibody (clone 331.1) is a sensitive and specific marker of pancreatic acinar cell carcinoma and pancreatic metaplasia.","date":"2008","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19066953","citation_count":60,"is_preprint":false},{"pmid":"17473310","id":"PMC_17473310","title":"CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB.","date":"2007","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/17473310","citation_count":58,"is_preprint":false},{"pmid":"18625728","id":"PMC_18625728","title":"The protein kinase C-responsive inhibitory domain of CARD11 functions in NF-kappaB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18625728","citation_count":58,"is_preprint":false},{"pmid":"22474286","id":"PMC_22474286","title":"Forkhead transcription factor FOXO3a protein activates nuclear factor κB through B-cell lymphoma/leukemia 10 (BCL10) protein and promotes tumor cell survival in serum deprivation.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22474286","citation_count":58,"is_preprint":false},{"pmid":"15845895","id":"PMC_15845895","title":"Nuclear expression of BCL10 or nuclear factor kappa B helps predict Helicobacter pylori-independent status of low-grade gastric mucosa-associated lymphoid tissue lymphomas with or without t(11;18)(q21;q21).","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15845895","citation_count":57,"is_preprint":false},{"pmid":"27071417","id":"PMC_27071417","title":"Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27071417","citation_count":55,"is_preprint":false},{"pmid":"15337797","id":"PMC_15337797","title":"Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas.","date":"2004","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15337797","citation_count":51,"is_preprint":false},{"pmid":"27777308","id":"PMC_27777308","title":"Molecular Determinants of Scaffold-induced Linear Ubiquitinylation of B Cell Lymphoma/Leukemia 10 (Bcl10) during T Cell Receptor and Oncogenic Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27777308","citation_count":50,"is_preprint":false},{"pmid":"30357852","id":"PMC_30357852","title":"Aphid effector Me10 interacts with tomato TFT7, a 14-3-3 isoform involved in aphid resistance.","date":"2018","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/30357852","citation_count":46,"is_preprint":false},{"pmid":"17371994","id":"PMC_17371994","title":"Bcl10 controls TCR- and FcgammaR-induced actin polymerization.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17371994","citation_count":46,"is_preprint":false},{"pmid":"23530562","id":"PMC_23530562","title":"BCL10 as a useful marker for pancreatic acinar cell carcinoma, especially using endoscopic ultrasound cytology specimens.","date":"2013","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/23530562","citation_count":46,"is_preprint":false},{"pmid":"16341151","id":"PMC_16341151","title":"MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells.","date":"2006","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/16341151","citation_count":45,"is_preprint":false},{"pmid":"28158919","id":"PMC_28158919","title":"Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28158919","citation_count":45,"is_preprint":false},{"pmid":"30022982","id":"PMC_30022982","title":"BCL10 - Bridging CARDs to Immune Activation.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30022982","citation_count":44,"is_preprint":false},{"pmid":"15213237","id":"PMC_15213237","title":"BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15213237","citation_count":43,"is_preprint":false},{"pmid":"17540779","id":"PMC_17540779","title":"Bcl10 mediates LPS-induced activation of NF-kappaB and IL-8 in human intestinal epithelial cells.","date":"2007","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17540779","citation_count":42,"is_preprint":false},{"pmid":"30429846","id":"PMC_30429846","title":"A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30429846","citation_count":41,"is_preprint":false},{"pmid":"21896478","id":"PMC_21896478","title":"The E3 ubiquitin ligase mind bomb-2 (MIB2) protein controls B-cell CLL/lymphoma 10 (BCL10)-dependent NF-κB activation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21896478","citation_count":41,"is_preprint":false},{"pmid":"17468049","id":"PMC_17468049","title":"Post-translational modifications regulate distinct functions of CARMA1 and BCL10.","date":"2007","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17468049","citation_count":40,"is_preprint":false},{"pmid":"16280327","id":"PMC_16280327","title":"A pathway for tumor necrosis factor-alpha-induced Bcl10 nuclear translocation. Bcl10 is up-regulated by NF-kappaB and phosphorylated by Akt1 and then complexes with Bcl3 to enter the nucleus.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16280327","citation_count":39,"is_preprint":false},{"pmid":"20466000","id":"PMC_20466000","title":"Lipopolysaccharide-induced activation of NF-κB non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20466000","citation_count":38,"is_preprint":false},{"pmid":"12091384","id":"PMC_12091384","title":"Protein kinase C-associated kinase (PKK) mediates Bcl10-independent NF-kappa B activation induced by phorbol ester.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12091384","citation_count":37,"is_preprint":false},{"pmid":"17052756","id":"PMC_17052756","title":"Bcl10 is phosphorylated on Ser138 by Ca2+/calmodulin-dependent protein kinase II.","date":"2006","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17052756","citation_count":36,"is_preprint":false},{"pmid":"24825920","id":"PMC_24825920","title":"T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24825920","citation_count":36,"is_preprint":false},{"pmid":"17785812","id":"PMC_17785812","title":"Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17785812","citation_count":35,"is_preprint":false},{"pmid":"18806265","id":"PMC_18806265","title":"Multiple protein domains mediate interaction between Bcl10 and MALT1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18806265","citation_count":34,"is_preprint":false},{"pmid":"17502353","id":"PMC_17502353","title":"Phosphorylation of Bcl10 negatively regulates T-cell receptor-mediated NF-kappaB activation.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17502353","citation_count":34,"is_preprint":false},{"pmid":"16123224","id":"PMC_16123224","title":"MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16123224","citation_count":34,"is_preprint":false},{"pmid":"30514565","id":"PMC_30514565","title":"Ubiquitination and phosphorylation of the CARD11-BCL10-MALT1 signalosome in T cells.","date":"2018","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30514565","citation_count":33,"is_preprint":false},{"pmid":"18941215","id":"PMC_18941215","title":"Loss of protein kinase C theta, Bcl10, or Malt1 selectively impairs proliferation and NF-kappa B activation in the CD4+ T cell subset.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18941215","citation_count":31,"is_preprint":false},{"pmid":"10408401","id":"PMC_10408401","title":"Bcl10 is not a target for frequent mutation in human carcinomas.","date":"1999","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10408401","citation_count":30,"is_preprint":false},{"pmid":"10582682","id":"PMC_10582682","title":"Point mutations and deletions of the Bcl10 gene in solid tumors and malignant lymphomas.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10582682","citation_count":30,"is_preprint":false},{"pmid":"14674990","id":"PMC_14674990","title":"No evidence of a correlation between BCL10 expression and API2-MALT1 gene rearrangement in ocular adnexal MALT lymphoma.","date":"2004","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/14674990","citation_count":30,"is_preprint":false},{"pmid":"19444310","id":"PMC_19444310","title":"COP9 signalosome controls the Carma1-Bcl10-Malt1 complex upon T-cell stimulation.","date":"2009","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/19444310","citation_count":29,"is_preprint":false},{"pmid":"18718996","id":"PMC_18718996","title":"Lipopolysaccharide activates NF-kappaB by TLR4-Bcl10-dependent and independent pathways in colonic epithelial cells.","date":"2008","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18718996","citation_count":29,"is_preprint":false},{"pmid":"29358699","id":"PMC_29358699","title":"GSK3β modulates NF-κB activation and RelB degradation through site-specific phosphorylation of BCL10.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29358699","citation_count":28,"is_preprint":false},{"pmid":"21513986","id":"PMC_21513986","title":"CaMKII targets Bcl10 in T-cell receptor induced activation of NF-κB.","date":"2011","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21513986","citation_count":27,"is_preprint":false},{"pmid":"16784987","id":"PMC_16784987","title":"Aberrant nuclear BCL10 expression and lack of t(11;18)(q21;q21) in primary cutaneous marginal zone B-cell lymphoma.","date":"2006","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16784987","citation_count":27,"is_preprint":false},{"pmid":"16648871","id":"PMC_16648871","title":"Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival.","date":"2006","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/16648871","citation_count":27,"is_preprint":false},{"pmid":"35658124","id":"PMC_35658124","title":"BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.","date":"2022","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35658124","citation_count":26,"is_preprint":false},{"pmid":"10408400","id":"PMC_10408400","title":"Lack of Bcl10 mutations in testicular germ cell tumours and derived cell lines.","date":"1999","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10408400","citation_count":26,"is_preprint":false},{"pmid":"29881386","id":"PMC_29881386","title":"Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29881386","citation_count":25,"is_preprint":false},{"pmid":"10408399","id":"PMC_10408399","title":"Mutations in Bcl10 are very rare in colorectal cancer.","date":"1999","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10408399","citation_count":24,"is_preprint":false},{"pmid":"25185127","id":"PMC_25185127","title":"Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling.","date":"2014","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/25185127","citation_count":22,"is_preprint":false},{"pmid":"31595055","id":"PMC_31595055","title":"Bcl10 is required for the development and suppressive function of Foxp3+ regulatory T cells.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31595055","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50032,"output_tokens":10958,"usd":0.157233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21793,"output_tokens":7577,"usd":0.149195,"stage2_stop_reason":"end_turn"},"total_usd":0.306428,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"BCL10 contains an N-terminal CARD domain that mediates homodimerization/oligomerization; CARD-mediated oligomerization is essential for both NF-κB activation and apoptosis induction. Wild-type BCL10 activates NF-κB and induces apoptosis, while C-terminal truncation mutants retain NF-κB activation but lose pro-apoptotic activity.\",\n      \"method\": \"Overexpression in 293/MCF7 cells, mutational analysis, NF-κB reporter assays, apoptosis assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, reporter assay, apoptosis readout) replicated across two independent papers (PMID:9989495, PMID:10319863)\",\n      \"pmids\": [\"9989495\", \"10319863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BCL10 (also called mE10/CIPER/CLAP/c-E10) contains an N-terminal CARD that forms homodimers; the C-terminal region binds pro-caspase-9 and promotes its autoproteolytic activation to induce apoptosis, with CARD-mediated oligomerization being essential for killing activity.\",\n      \"method\": \"Overexpression in MCF-7 cells, co-immunoprecipitation, mutational analysis, caspase processing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of caspase-9 activation, mutagenesis, replicated across multiple 1999 papers (PMID:10187815, PMID:10187770, PMID:10364242)\",\n      \"pmids\": [\"10187815\", \"10187770\", \"10364242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BCL10 CARD domain activates NF-κB through a NIK-dependent pathway upstream of IKKα; the CARD is both necessary and sufficient for NF-κB activation and for homodimerization.\",\n      \"method\": \"Mutational analysis, dominant-negative NIK/IκBα constructs, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis plus epistasis with dominant-negative constructs, replicated across multiple 1999 papers (PMID:10187770, PMID:10364242)\",\n      \"pmids\": [\"10187770\", \"10364242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BCL10 is a positive regulator of antigen receptor-induced NF-κB activation in B and T lymphocytes. BCL10-deficient mice show complete absence of antigen receptor-induced NF-κB activation while retaining normal Ca2+ signaling, MAPK, and AP-1 activation, placing BCL10 specifically in the NF-κB branch downstream of antigen receptors.\",\n      \"method\": \"Bcl10 knockout mice, lymphocyte stimulation assays, NF-κB activation assays, genetic epistasis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined NF-κB-specific phenotype, replicated by multiple labs\",\n      \"pmids\": [\"11163238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BCL10 and MALT1 form a specific protein complex; BCL10 mediates oligomerization and activation of the MALT1 caspase-like domain, and together they synergistically activate NF-κB through the IKK complex. BCL10 bridges the BIMP1/MALT1 interaction in a ternary complex.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assays, dominant-negative mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, reconstitution of ternary complex, replicated across multiple papers (PMID:11262391, PMID:11387339)\",\n      \"pmids\": [\"11262391\", \"11387339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CARD11/CARMA1 binds BCL10 via CARD-CARD interaction, induces phosphorylation of BCL10, and translocates BCL10 from cytoplasm to perinuclear structures, thereby activating NF-κB. CARD11 and CARD14 both associate specifically with the BCL10 CARD domain.\",\n      \"method\": \"Co-immunoprecipitation, co-transfection, subcellular localization by immunofluorescence, NF-κB reporter assays\",\n      \"journal\": \"FEBS letters / The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, localization experiment with functional consequence, replicated across multiple papers (PMID:11356195, PMID:11278692)\",\n      \"pmids\": [\"11356195\", \"11278692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CARD9 directly interacts with the BCL10 CARD domain (but not other CARD-containing proteins), forms a pre-existing signaling complex with endogenous BCL10, and activates NF-κB as an upstream activator of BCL10.\",\n      \"method\": \"Mammalian two-hybrid, co-immunoprecipitation of endogenous proteins, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP plus two-hybrid, single lab\",\n      \"pmids\": [\"11053425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BCL10 activates NF-κB by targeting NEMO/IKKγ for K63-linked polyubiquitination, requiring MALT1 (paracaspase) and UBC13 as a ubiquitin-conjugating enzyme. A NEMO mutant unable to be ubiquitinated blocks BCL10-induced NF-κB activation.\",\n      \"method\": \"siRNA knockdown, ubiquitination assays, NEMO ubiquitination-site mutants, NF-κB reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination reconstitution, mutagenesis of NEMO ubiquitination sites, multiple orthogonal methods\",\n      \"pmids\": [\"14695475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation downstream of BCL10 and MALT1. Only oligomeric (high-molecular-weight) forms of BCL10 and MALT1 can activate IKK in vitro. MALT1 oligomers bind TRAF6, induce TRAF6 oligomerization, and activate TRAF6 ligase activity to polyubiquitinate NEMO.\",\n      \"method\": \"In vitro reconstitution with purified proteins, RNAi silencing, IKK activation assays, gel filtration to isolate oligomers\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full in vitro reconstitution with purified components plus RNAi validation, multiple orthogonal methods\",\n      \"pmids\": [\"15125833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA1 recruits BCL10 and IKKβ into lipid rafts of the immunological synapse in a CD3/CD28-dependent manner; CARMA1 membrane association is required for this recruitment, and a CARMA1 mutant unable to associate with BCL10 fails to rescue NF-κB activation.\",\n      \"method\": \"Lipid raft fractionation, immunological synapse imaging, CARMA1-deficient T cell complementation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular fractionation with functional consequence, genetic rescue experiments in CARMA1-deficient cells\",\n      \"pmids\": [\"14673152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BCL10 degradation following TCR/PKC stimulation occurs via the lysosomal pathway (not proteasome), requires an intact CARD domain, and is promoted by HECT-domain ubiquitin ligases NEDD4 and Itch, which ubiquitinate BCL10. This degradation selectively terminates IKK/NF-κB signaling.\",\n      \"method\": \"Proteasome inhibitor treatment, lysosome fractionation, ubiquitin ligase overexpression/knockdown, NF-κB activity assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and biochemical fractionation, single lab\",\n      \"pmids\": [\"15082780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IKKβ plays a dual role at the CBM complex: it is required for initial CBM complex formation, but upon engagement IKKβ phosphorylates BCL10 at its C-terminus, disrupting BCL10/MALT1 association and BCL10-mediated IKKγ ubiquitination, thereby providing negative feedback. Mutation of IKKβ phosphorylation sites on BCL10 enhances NF-κB target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, IKKβ phosphorylation site mutagenesis, primary T cell NF-κB reporter assays, IL-2/TNFα measurement\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis validated in primary T cells, multiple orthogonal methods\",\n      \"pmids\": [\"16818229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"cIAP2 functions as an E3 ubiquitin ligase for BCL10, targeting it for degradation and thereby inhibiting antigen receptor-mediated cytokine production. The cIAP2-MALT1 fusion protein lacks E3 activity, leading to BCL10 stabilization in MALT lymphomas.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, BCL10 protein stability assays, cytokine production assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E3 activity toward BCL10, mutagenesis, single lab\",\n      \"pmids\": [\"16395405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCL10 and MALT1 are essential for FcεRI-mediated NF-κB activation and pro-inflammatory cytokine production in mast cells, but are dispensable for degranulation and leukotriene secretion, demonstrating that BCL10 selectively controls the NF-κB arm downstream of FcεRI.\",\n      \"method\": \"Bcl10−/− and Malt1−/− mice, mast cell stimulation, cytokine ELISA, degranulation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts with defined parallel functional readouts dissecting pathway branches\",\n      \"pmids\": [\"16432253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA3/BCL10/MALT1 form a signalosome that mediates angiotensin II receptor (GPCR)-dependent NF-κB activation in hepatocytes and vascular cells, acting through IKKγ ubiquitination. BCL10-deficient mice show defective hepatic cytokine production after Ang II treatment.\",\n      \"method\": \"Dominant-negative mutants, RNAi, gene targeting (Bcl10−/− mice), IKKγ ubiquitination assay, cytokine ELISA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo plus RNAi plus dominant-negative, multiple orthogonal approaches\",\n      \"pmids\": [\"17101977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCL10 and MALT1 are required for lysophosphatidic acid (LPA)-induced NF-κB activation and IL-6 production downstream of G protein-coupled receptors in non-immune cells, cooperating with PKC. BCL10/MALT1 are dispensable for LPA-activated JNK, p38, ERK, and Akt.\",\n      \"method\": \"Bcl10−/− and Malt1−/− mouse embryonic fibroblasts, IκBα degradation assays, IL-6 ELISA, kinase pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout cells with parallel pathway dissection, multiple functional readouts\",\n      \"pmids\": [\"17095601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BCL10 is phosphorylated at Ser138 by CaMKII following TCR stimulation; phosphorylation at this residue by CaMKII is required for CaMKII's ability to regulate interactions within the Carma1-BCL10-MALT1 complex and for signal-induced ubiquitinations of BCL10 and IKKγ.\",\n      \"method\": \"In vitro kinase assay (CaMKII + BCL10), CaMKII inhibitor KN93, CaMKII siRNA, S138A mutagenesis, NF-κB reporter assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro phosphorylation assay with mutagenesis, pharmacological and RNAi validation, single lab\",\n      \"pmids\": [\"17052756\", \"21513986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Phosphorylation of BCL10 at Ser138 negatively regulates NF-κB activation: the S138A mutation impairs TCR-induced ubiquitination and subsequent degradation of BCL10, prolonging NF-κB activation and enhancing IL-2 production.\",\n      \"method\": \"Phosphorylation site mutagenesis (S138A), ubiquitination assays, NF-κB reporter assays, IL-2 ELISA\",\n      \"journal\": \"Journal of immunology / Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of phosphorylation site with mechanistic downstream readouts, replicated across two papers (PMID:17371994, PMID:17502353)\",\n      \"pmids\": [\"17371994\", \"17502353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IKK complex phosphorylates BCL10 after TCR stimulation and causes its proteolysis via the β-TrCP ubiquitin ligase/proteasome pathway, providing a negative feedback loop. BCL10 mutants at IKK phosphorylation sites are resistant to degradation, accumulate in the nucleus, and increase IL-2 production.\",\n      \"method\": \"In vitro IKK kinase assay, proteasome inhibitors, β-TrCP overexpression, phosphorylation-site mutagenesis, IL-2 measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay plus mutagenesis plus in-cell validation, single lab\",\n      \"pmids\": [\"17213322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BCL10 (but not CARMA1) controls TCR-induced and FcγR-induced actin polymerization independently of NF-κB activation. Phosphorylation-deficient S138A BCL10 specifically inhibits TCR-induced actin polymerization without affecting NF-κB. BCL10 silencing impairs phagocytosis in monocytes.\",\n      \"method\": \"BCL10 siRNA, S138A mutagenesis, F-actin staining, phagocytosis assays, NF-κB reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus phospho-site mutagenesis dissecting NF-κB vs. actin functions, single lab\",\n      \"pmids\": [\"17371994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"K63-linked polyubiquitination of BCL10 at residues K31 and K63 is required for NEMO/IKKγ binding and NF-κB activation following TCR stimulation. Mutation of these ubiquitination sites prevents NEMO recruitment without affecting CBM complex assembly.\",\n      \"method\": \"K63-ubiquitin linkage-specific assays, BCL10 ubiquitination site mutagenesis (K31R, K63R), NEMO binding assay, NF-κB reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis with mechanistic dissection of CBM assembly vs. NEMO recruitment, rigorous controls\",\n      \"pmids\": [\"18287044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Bcl10-MALT1 interaction involves multiple protein domains: a 13-aa region C-terminal to the Bcl10 CARD interacts with MALT1 Ig-like domains, and additionally the MALT1 death domain and BCL10 CARD (especially residues D80 and E84 of helix 5) contribute to the interaction. CARD mutations that disrupt folding strongly impair BCL10-MALT1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, FRET in T cells, point mutagenesis of conserved BCL10 CARD residues, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP plus mutagenesis, single lab\",\n      \"pmids\": [\"18806265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CARD11 recruits multiple signaling cofactors (BCL10, TRAF6, TAK1, IKKγ, caspase-8) through its CARD and coiled-coil domains in a signal-inducible manner; BCL10 and MALT1 are independently recruited to CARD11 and can associate with certain cofactors independently of one another.\",\n      \"method\": \"RNAi rescue assays, co-immunoprecipitation in BCL10- and MALT1-deficient cells, NF-κB reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue plus Co-IP in deficient cell lines, single lab\",\n      \"pmids\": [\"18625728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RIP2 kinase associates with BCL10 following TCR engagement and phosphorylates BCL10. RIP2-deficient T cells show defective BCL10 phosphorylation and NF-κB activation; kinase-dead RIP2 cannot rescue NF-κB activation in Rip2−/− fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, Rip2−/− mice, kinase-dead mutant complementation, NF-κB assays, BCL10 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus kinase-dead rescue plus Co-IP, single lab\",\n      \"pmids\": [\"14638696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BCL10 interacts with Pellino2 downstream of TLR4 in response to LPS; BCL10 is recruited to TLR4 signaling complexes, and this recruitment is negatively regulated by SOCS3. BCL10-deficient macrophages show defective LPS-induced NF-κB activation while AP-1 and Elk-1 signaling remain intact.\",\n      \"method\": \"Co-immunoprecipitation, BCL10-deficient macrophage cell line, SOCS3 overexpression, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in TLR4 complex plus genetic deficiency cell line, single lab\",\n      \"pmids\": [\"15213237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCL10 and MALT1 are required for NK cell-mediated NF-κB and JNK/p38 MAPK activation downstream of ITAM-coupled receptors (NK1.1, Ly49D, Ly49H, NKG2D), and depend on CARMA1 (not CARD9). These cascades selectively control cytokine/chemokine production but not cytotoxicity.\",\n      \"method\": \"Bcl10−/−, Malt1−/−, Carma1−/−, Card9−/− primary NK cells, cytokine production assays, cytotoxicity assays, NF-κB reporter assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four independent genetic knockouts with parallel functional dissection of cytokine vs. cytotoxicity branches\",\n      \"pmids\": [\"18192506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA1-BCL10 complex selectively regulates JNK2 (not JNK1) after TCR stimulation: BCL10 is inducibly associated with JNK2 and acts as a JIP-like scaffold to assemble JNK2, MKK7, and TAK1 kinases, regulating c-Jun protein levels.\",\n      \"method\": \"Co-immunoprecipitation, CARMA1/BCL10 knockout cells, JNK isoform-specific analysis, kinase assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic evidence plus Co-IP of endogenous complex, single lab\",\n      \"pmids\": [\"17189706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCL10 interacts with IRAK-1 upstream in the TLR4 pathway; upon BCL10 dissociation from IRAK-1, BCL10 translocates to cytosol with TRAF6 and TAK1 via a direct BCL10-Pellino2 interaction. BCL10 oligomerization is a prerequisite for its function in LPS-induced NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA against MALT1, subcellular fractionation, NF-κB activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus fractionation plus RNAi, single lab\",\n      \"pmids\": [\"16831874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Calcineurin (Ca2+-dependent phosphatase) directly dephosphorylates BCL10 in vivo and in vitro and interacts with the CBM complex; calcineurin activity positively regulates CBM complex formation and TCR-induced NF-κB. BCL10 is hyperphosphorylated when calcineurin is inhibited by CsA or FK506.\",\n      \"method\": \"In vitro phosphatase assay (calcineurin + BCL10), calcineurin A siRNA, CsA/FK506 treatment, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro dephosphorylation assay, pharmacological and siRNA validation, single lab\",\n      \"pmids\": [\"21199863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E3 ubiquitin ligase MIB2 directly interacts with BCL10, promotes autoubiquitination and ubiquitination of IKKγ/NEMO, and recruits/activates TAK1 as part of the activated BCL10 complex. MIB2 knockdown inhibits BCL10-dependent NF-κB activation.\",\n      \"method\": \"Proteomic identification, in vitro pulldown, overexpression NF-κB assays, MIB2 knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pulldown plus overexpression/knockdown, single lab\",\n      \"pmids\": [\"21896478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BCL10 has an NF-κB-independent role in actin and membrane remodeling downstream of FcγR in macrophages. BCL10 depletion impairs Rac1 and PI3K activation and leads to abortive phagocytic cups. BCL10 forms a complex with clathrin adaptors AP1 and EpsinR and is required to deliver the OCRL phosphatase (which regulates PI(4,5)P2 and F-actin) to the phagocytic cup.\",\n      \"method\": \"BCL10 depletion by siRNA, phagocytosis assays, Rac1/PI3K activation assays, co-immunoprecipitation with AP1/EpsinR, PI(4,5)P2 imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue with F-actin depolymerizing drugs, multiple readouts, single lab\",\n      \"pmids\": [\"23153494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TCR engagement triggers selective autophagy of BCL10 in effector (but not naive) T cells, requiring K63-polyubiquitination of BCL10 and subsequent association with the autophagy adaptor p62. p62 binding is required for both BCL10 signaling to NF-κB and gradual BCL10 degradation; blockade of BCL10 autophagy enhances NF-κB activation.\",\n      \"method\": \"Autophagy inhibition, ubiquitin linkage-specific assays, p62 knockout/knockdown, BCL10 degradation assays, NF-κB activation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ubiquitination assay, genetic p62 depletion, autophagy blockade) with clear mechanistic model\",\n      \"pmids\": [\"22658522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The reconstituted CBM signalosome forms a helical filamentous assembly: CARMA1 nucleates BCL10 filament formation through CARD-CARD interactions in a cooperative, threshold-sensitive manner; MALT1 binds BCL10 filaments and is activated; structure of the BCL10 CARD filament was determined by crystallography, NMR, and EM. Structure-guided mutagenesis confirmed interfaces required for BCL10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells.\",\n      \"method\": \"Cryo-EM, crystallography, NMR, in vitro reconstitution of CBM filament, structure-guided mutagenesis, NF-κB reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic structure plus reconstitution plus mutagenesis in cells, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24074955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BCL10 polymerizes in a unidirectional manner as shown by time-lapse confocal imaging; cryo-EM structure of the BCL10 CARD filament at 4.0 Å resolution redefines CARD-CARD interfaces. CARMA1 serves as a hub forming star-shaped filamentous BCL10 networks and decreases BCL10 polymerization lag time. MALT1 immediately dimerizes on BCL10 filaments, and TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies.\",\n      \"method\": \"Cryo-EM at 4.0 Å, time-lapse confocal imaging, EM of MALT1 and TRAF6 decoration of filaments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic structure plus live-cell imaging plus EM of higher-order assemblies, multiple orthogonal methods\",\n      \"pmids\": [\"29382759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A cytosolic p62-BCL10-MALT1-IKK signalosome forms in effector T cells upon TCR stimulation; the active IKK complex is a component of this signalosome; phosphorylated IκBα and NF-κB are transiently recruited before nuclear NF-κB translocation. p62-dependent clustering is required for NF-κB activation in effector T cells.\",\n      \"method\": \"Co-immunoprecipitation, p62-deficient T cells, confocal imaging of signalosome clusters, IKK activity assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic p62 knockout plus biochemical Co-IP of endogenous complex, single lab\",\n      \"pmids\": [\"24825920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BCL10 is NOT required for TCR/CD28-induced mTOR activation in T cells; this distinguishes the BCL10 requirement for NF-κB from a CARMA1/MALT1-dependent but BCL10-independent pathway to mTOR signaling.\",\n      \"method\": \"BCL10-deficient T cells, mTOR pathway activation assays, metabolic flux assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined negative result for mTOR, single lab; negative finding mechanistically informative\",\n      \"pmids\": [\"24917592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MALT1 contains nuclear export signals (NES) and controls the cytoplasmic localization of BCL10; MALT1 is involved in nuclear export of BCL10, shuttling between nucleus and cytoplasm. Leptomycin B (NES inhibitor) retains MALT1 and BCL10 in the nucleus.\",\n      \"method\": \"Deletion mutagenesis of MALT1 NES, leptomycin B treatment, subcellular fractionation and imaging\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and mutagenesis-based localization experiments, single lab\",\n      \"pmids\": [\"16123224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BCL10 undergoes nuclear translocation in response to TNFα: Akt1 phosphorylates BCL10 at Ser218 and Ser231, and phosphorylated BCL10 then complexes with Bcl3 to enter the nucleus. An NF-κB-binding site in the BCL10 5'-UTR drives NF-κB-dependent BCL10 upregulation.\",\n      \"method\": \"Chromatin immunoprecipitation, EMSA, Akt1 kinase assay, Bcl3 co-immunoprecipitation, Akt1 inhibitor, Bcl3 depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro Akt1 phosphorylation of BCL10, Co-IP with Bcl3, ChIP, inhibitor validation, single lab\",\n      \"pmids\": [\"16280327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS activates the non-canonical NF-κB pathway (RelB/p52) in colonic epithelial cells through BCL10; phosphorylation of BCL10 Ser138 is required for NIK phosphorylation and subsequent RelB/p52 nuclear translocation. Mutation of Ser138 or Ser218 reduces both canonical and non-canonical NF-κB activation.\",\n      \"method\": \"BCL10 siRNA, BCL10 phosphorylation-site mutagenesis (S138G, S218G), nuclear RelB/p52 assays, phospho-NIK assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of specific phosphorylation sites with multiple NF-κB pathway readouts, single lab\",\n      \"pmids\": [\"20466000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"COP9 signalosome subunit CSN5 interacts with MALT1 and CARMA1; TCR activation recruits CSN to the CBM complex. The CSN is required for maintaining BCL10 stability in response to T cell activation and for TCR-induced IKK activation.\",\n      \"method\": \"Co-immunoprecipitation, CSN5 siRNA knockdown, BCL10 stability assays, IKK activation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of endogenous complex plus siRNA, single lab\",\n      \"pmids\": [\"19444310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCL10 undergoes TCR-induced conjugation with linearly-linked (M1) polyubiquitin chains (Lin(Ub)n-BCL10) at lysines K17, K31, and K63; linear ubiquitination requires CARD11, MALT1, and the HOIP subunit of LUBAC. Lin(Ub)n-BCL10 is required for NEMO/IKK recruitment. CARD11 co-recruits BCL10 with HOIP to bring substrate to enzyme.\",\n      \"method\": \"Linkage-specific ubiquitin assays, BCL10 lysine mutagenesis, HOIP/LUBAC knockdown, CARD11 co-IP experiments, NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — linear ubiquitin-specific assays, site-directed mutagenesis at three lysines, genetic depletion, mechanistic model with substrate-enzyme co-recruitment\",\n      \"pmids\": [\"27777308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GSK3β regulates CBM complex formation through site-specific phosphorylation of BCL10; GSK3β inhibition reduces BCL10 phosphorylation, impairs CBM assembly, and consequently reduces MALT1 protease-dependent cleavage of substrates (BCL10, CYLD, RelB), IκBα degradation, and NF-κB activity.\",\n      \"method\": \"GSK3β pharmacological inhibitors (SB216763, SB415286), GSK3β RNAi, BCL10 phosphorylation assays, MALT1 substrate cleavage assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus RNAi plus multiple downstream readouts, single lab\",\n      \"pmids\": [\"29358699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in regulatory T cells and controls their suppressive function; BCL10-dependent MALT1 protease activity is specifically required for Treg suppressive function. Acute BCL10 deletion in mature Tregs impairs suppression and causes lethal autoimmunity.\",\n      \"method\": \"Conditional BCL10 knockout in Tregs (Bcl10fl/fl Foxp3cre), Treg suppression assays, Rag1−/− colitis transfer, gene expression profiling, MALT1 inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout with defined suppression phenotype plus MALT1 inhibitor validation, multiple orthogonal readouts\",\n      \"pmids\": [\"31138793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BCL10 mutations in ABC-DLBCL fall into two biochemically distinct classes: (1) CARD missense mutations enhance BCL10 filament formation via glutamine network structures that stabilize filaments; (2) C-terminal truncating mutations abrogate a MALT1 inhibitory motif, trapping MALT1 in activated filament-bound state. Both classes confer BTK inhibitor resistance, while truncating (not CARD) mutants are hypersensitive to MALT1 inhibitors.\",\n      \"method\": \"Structural analysis, BCL10 polymerization assays, MALT1 activity assays, BTK inhibitor/MALT1 inhibitor drug sensitivity testing in primary lymphoma and cell lines\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-function analysis with biochemical polymerization assays, mutagenesis, and pharmacological validation across multiple mutation classes\",\n      \"pmids\": [\"35658124\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BCL10 is a CARD-domain adaptor protein that, upon antigen receptor or GPCR stimulation, is recruited by CARMA/CARD scaffold proteins (CARMA1 in lymphocytes, CARMA3 in non-immune cells) to nucleate cooperative BCL10 CARD filament formation, which scaffolds MALT1 dimerization and TRAF6 recruitment, leading to K63-linked and linear polyubiquitination of BCL10 and NEMO/IKKγ (mediated by UBC13/LUBAC/HOIP), TAK1 activation, and canonical IKK/NF-κB activation; BCL10 activity is tightly regulated by phosphorylation (by CaMKII, RIP2, IKKβ, and Akt1), ubiquitination (by NEDD4/Itch, cIAP2, MIB2), and degradation via lysosomal/autophagic (p62-dependent) and proteasomal (β-TrCP-dependent) pathways, with calcineurin providing positive feedback through BCL10 dephosphorylation; independently of NF-κB, BCL10 controls actin polymerization and phagocytic cup closure via a complex with AP1/EpsinR and the OCRL phosphatase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BCL10 is a CARD-domain adaptor protein that serves as the central signal-amplifying scaffold linking antigen and G protein-coupled receptors to canonical NF-κB activation [#3, #14]. Its N-terminal CARD mediates homo-oligomerization, an activity essential for both NF-κB activation and, in overexpression settings, caspase-9-dependent apoptosis [#0, #1, #2]. Upon receptor engagement, CARMA/CARD scaffolds (CARMA1 in lymphocytes, CARMA3 in non-immune cells, CARD9 in myeloid contexts) bind the BCL10 CARD and nucleate cooperative, unidirectional BCL10 CARD filament assembly, which recruits BCL10 to membrane lipid rafts at the immunological synapse and templates MALT1 dimerization and TRAF6 decoration into a higher-order CBM signalosome [#5, #6, #9, #32, #33]. Within this assembly BCL10 oligomers, together with MALT1 paracaspase activity, drive TRAF6/UBC13- and LUBAC/HOIP-dependent K63-linked and linear (M1) polyubiquitination of BCL10 itself (at K17/K31/K63) and of NEMO/IKKγ, recruiting and activating the IKK complex via TAK1 to trigger IκBα degradation and NF-κB nuclear translocation [#7, #8, #20, #40]. BCL10 signaling is selective for the NF-κB branch, being dispensable for Ca2+ flux, MAPK/AP-1, and mTOR activation downstream of these receptors [#3, #15, #35]. Signal output is tightly bounded by a phosphorylation and degradation network: CaMKII (Ser138), RIP2, IKKβ, and Akt1 phosphorylate BCL10 with both activating and feedback-terminating consequences, calcineurin dephosphorylates BCL10 to sustain CBM assembly, and BCL10 is degraded through NEDD4/Itch- and cIAP2-driven lysosomal, p62-dependent autophagic, and β-TrCP-dependent proteasomal routes [#10, #11, #12, #16, #17, #18, #28, #31]. BCL10 also performs an NF-κB-independent function in actin and membrane remodeling, controlling Fcγ/TCR-induced actin polymerization and phagocytic cup closure through a complex with the clathrin adaptors AP1/EpsinR that delivers the OCRL phosphatase to the phagocytic cup [#19, #30]. Activating CARD missense and C-terminal truncating BCL10 mutations drive constitutive CBM signaling in ABC-DLBCL and confer distinct therapeutic vulnerabilities [#43].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the founding molecular activity of BCL10: that its N-terminal CARD drives self-oligomerization, which is required both to activate NF-κB and to engage caspase-9-dependent apoptosis, defining BCL10 as a bifunctional CARD adaptor.\",\n      \"evidence\": \"Overexpression, mutational analysis, NF-κB reporter and caspase processing assays in 293/MCF-7 cells\",\n      \"pmids\": [\"9989495\", \"10319863\", \"10187815\", \"10187770\", \"10364242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed in overexpression systems; physiological relevance of the apoptotic arm not established\", \"Did not identify upstream receptors or scaffolds engaging BCL10\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed BCL10 in the NF-κB cascade upstream of IKKα via a NIK-dependent route, showing the CARD is both necessary and sufficient for signaling.\",\n      \"evidence\": \"Dominant-negative NIK/IκBα constructs and NF-κB reporter assays\",\n      \"pmids\": [\"10187770\", \"10364242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor input or direct downstream ubiquitination targets\", \"NIK-dependence later refined to canonical IKK activation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic knockout demonstrated that BCL10 is specifically required for antigen-receptor-induced NF-κB in lymphocytes while sparing Ca2+, MAPK, and AP-1 signaling, fixing BCL10 to the NF-κB branch in vivo.\",\n      \"evidence\": \"Bcl10-deficient mice with lymphocyte stimulation and pathway-specific NF-κB assays\",\n      \"pmids\": [\"11163238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular bridge between the receptor and BCL10\", \"Mechanism of NF-κB-branch selectivity unexplained\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the core CBM assembly by showing BCL10 bridges CARMA-type scaffolds to MALT1, oligomerizing and activating the MALT1 caspase-like domain for synergistic IKK-dependent NF-κB activation.\",\n      \"evidence\": \"Co-immunoprecipitation, ternary complex reconstitution, dominant-negative NF-κB reporter assays; CARMA1/CARD11 CARD-CARD binding and BCL10 translocation imaging\",\n      \"pmids\": [\"11262391\", \"11387339\", \"11356195\", \"11278692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how MALT1 oligomerization leads to IKK activation biochemically\", \"Structural basis of CARD-CARD nucleation unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the biochemical output of the CBM complex: BCL10/MALT1 direct K63-linked polyubiquitination of NEMO/IKKγ via UBC13, defining ubiquitin signaling as the link to IKK activation.\",\n      \"evidence\": \"siRNA knockdown, in vitro ubiquitination, NEMO ubiquitination-site mutants, NF-κB reporter assays; RIP2 association/phosphorylation of BCL10 from knockout mice\",\n      \"pmids\": [\"14695475\", \"14638696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible not yet pinned to TRAF6\", \"Order of BCL10 vs NEMO ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reconstituted the activation mechanism with purified components, showing oligomeric BCL10/MALT1 binds and activates TRAF6 ligase, which polyubiquitinates NEMO and engages TAK1 to activate IKK, and localized assembly to immunological-synapse lipid rafts.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins, gel filtration of oligomers, RNAi; lipid raft fractionation and CARMA1-deficient T cell complementation\",\n      \"pmids\": [\"15125833\", \"14673152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not visualize the higher-order architecture of the active complex\", \"How oligomerization threshold is set in cells unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed signal termination logic by showing TCR-induced lysosomal degradation of BCL10 driven by HECT E3 ligases NEDD4/Itch, selectively shutting down NF-κB.\",\n      \"evidence\": \"Proteasome inhibitors, lysosome fractionation, E3 ligase overexpression/knockdown, NF-κB assays\",\n      \"pmids\": [\"15082780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; relative contribution of lysosomal vs other degradation routes unquantified\", \"Ubiquitin linkage type targeting BCL10 to lysosome not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended BCL10 function beyond antigen receptors to innate TLR4 signaling, showing recruitment to TLR4 complexes and a requirement for LPS-induced NF-κB, with SOCS3 as a negative regulator.\",\n      \"evidence\": \"Co-IP, BCL10-deficient macrophage line, SOCS3 overexpression, NF-κB reporter assays; IRAK-1/Pellino2 interactions and fractionation\",\n      \"pmids\": [\"15213237\", \"16831874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TLR4-to-BCL10 connection less defined than antigen-receptor axis\", \"Single-lab Co-IP and fractionation without reconstitution\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Uncovered nucleocytoplasmic regulation of BCL10: MALT1 NES-driven export controls BCL10 cytoplasmic localization, while Akt1 phosphorylation (Ser218/Ser231) and Bcl3 binding drive TNFα-induced BCL10 nuclear entry, with NF-κB autoregulating BCL10 transcription.\",\n      \"evidence\": \"MALT1 NES mutagenesis and leptomycin B; Akt1 kinase assay, Bcl3 Co-IP, ChIP/EMSA, inhibitor validation\",\n      \"pmids\": [\"16123224\", \"16280327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of nuclear BCL10 not fully defined\", \"Single-lab studies for each localization branch\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Generalized BCL10 to GPCR signaling via CARMA3-BCL10-MALT1 signalosomes (angiotensin II, LPA) and to multiple immune effector contexts (mast cells, NK cells), each selectively controlling the NF-κB/cytokine arm while sparing other outputs.\",\n      \"evidence\": \"Bcl10-/- mice and MEFs, dominant-negative/RNAi, IKKγ ubiquitination and cytokine assays, parallel pathway dissection in mast and NK cells\",\n      \"pmids\": [\"17101977\", \"17095601\", \"16432253\", \"18192506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific scaffold partners for each receptor not all mapped\", \"Mechanism of NF-κB-branch selectivity remained unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a multi-kinase phosphoregulatory network on BCL10 — CaMKII (Ser138) priming ubiquitination, IKKβ and the IKK complex driving negative-feedback disassembly and β-TrCP/proteasomal degradation — quantitatively tuning NF-κB output.\",\n      \"evidence\": \"In vitro kinase assays, phospho-site mutagenesis (S138A, IKK sites), ubiquitination/degradation and IL-2 assays in primary T cells\",\n      \"pmids\": [\"16818229\", \"17052756\", \"21513986\", \"17371994\", \"17502353\", \"17213322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of competing kinases not fully resolved\", \"Some phospho-site assignments from single labs\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed BCL10 also scaffolds JNK2 signaling and identified cIAP2 as an E3 ligase degrading BCL10, with loss of this activity in the cIAP2-MALT1 lymphoma fusion stabilizing BCL10.\",\n      \"evidence\": \"Endogenous Co-IP and JNK isoform-specific kinase assays; in vitro ubiquitination, stability and cytokine assays\",\n      \"pmids\": [\"17189706\", \"16395405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JNK2 scaffolding role from single lab\", \"Physiological substrate scope of cIAP2 toward BCL10 not generalized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Separated BCL10's NF-κB function from a distinct, phosphorylation-dependent role in actin polymerization and phagocytosis, showing S138A selectively blocks actin remodeling without affecting NF-κB.\",\n      \"evidence\": \"BCL10 siRNA, S138A mutagenesis, F-actin staining, phagocytosis and NF-κB reporter assays\",\n      \"pmids\": [\"17371994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector machinery linking BCL10 to actin not yet identified\", \"Single-lab knockdown study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the ubiquitin code on BCL10 by showing K63-linked ubiquitination at K31/K63 specifically mediates NEMO recruitment downstream of CBM assembly, separating complex formation from IKK recruitment; refined the BCL10 CARD-MALT1 interaction interfaces; and mapped CARD11 cofactor recruitment.\",\n      \"evidence\": \"Linkage-specific ubiquitin assays, lysine mutagenesis, NEMO-binding assays; FRET, Co-IP, point mutagenesis and modeling; RNAi rescue in deficient cells\",\n      \"pmids\": [\"18287044\", \"18806265\", \"18625728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase placing these chains on BCL10 not definitively assigned\", \"Interaction-mapping studies single-lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established positive-feedback dephosphorylation by calcineurin sustaining CBM assembly, and identified MIB2 as an additional BCL10-interacting E3 promoting NEMO ubiquitination and TAK1 activation.\",\n      \"evidence\": \"In vitro phosphatase assay, calcineurin RNAi and CsA/FK506; proteomic identification, pulldown, knockdown NF-κB assays\",\n      \"pmids\": [\"21199863\", \"21896478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both single-lab; integration with the IKKβ/β-TrCP negative arms not modeled\", \"Substrate residues dephosphorylated by calcineurin not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistically defined the NF-κB-independent membrane-remodeling role, showing BCL10 partners with AP1/EpsinV clathrin adaptors to deliver OCRL phosphatase and drive Rac1/PI3K-dependent phagocytic cup closure; and revealed selective autophagy as a degradation/signaling node requiring K63-ubiquitin and p62.\",\n      \"evidence\": \"siRNA depletion, phagocytosis/Rac1/PI3K assays, AP1/EpsinR Co-IP, PI(4,5)P2 imaging; autophagy inhibition, p62 knockout, BCL10 degradation/NF-κB assays\",\n      \"pmids\": [\"23153494\", \"22658522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AP1/EpsinR-OCRL pathway from single lab\", \"How phosphorylation gates the choice between NF-κB and actin functions unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural mechanism: CARMA1 nucleates cooperative, threshold-sensitive, unidirectional BCL10 CARD filament formation that templates MALT1 dimerization/activation and TRAF6 decoration into higher-order CBM assemblies.\",\n      \"evidence\": \"Cryo-EM, crystallography, NMR, in vitro filament reconstitution, structure-guided mutagenesis with NF-κB readouts; live-cell time-lapse imaging of polymerization\",\n      \"pmids\": [\"24074955\", \"29382759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitination machinery docks onto the filament structurally not resolved\", \"In vivo filament dynamics in primary cells not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined effector-T-cell-specific signalosome wiring (p62-BCL10-MALT1-IKK clustering) and sharpened the functional boundary of BCL10 by showing it is dispensable for CARMA1/MALT1-dependent mTOR activation.\",\n      \"evidence\": \"Co-IP, p62-deficient T cells, confocal imaging, IKK assays; BCL10-deficient T cell mTOR/metabolic assays\",\n      \"pmids\": [\"24825920\", \"24917592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both single-lab\", \"Molecular basis distinguishing BCL10-dependent NF-κB from BCL10-independent mTOR branch unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified linear (M1) ubiquitination of BCL10 at K17/K31/K63 by LUBAC/HOIP, co-recruited with substrate by CARD11, as a required step for NEMO/IKK recruitment, adding a second ubiquitin chain type to BCL10 signaling.\",\n      \"evidence\": \"Linkage-specific ubiquitin assays, lysine mutagenesis, HOIP/LUBAC knockdown, CARD11 Co-IP, NF-κB reporter assays\",\n      \"pmids\": [\"27777308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between K63 and M1 chains on the same lysines not deconvolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added GSK3β as an upstream kinase whose site-specific phosphorylation of BCL10 promotes CBM assembly and downstream MALT1 protease activity.\",\n      \"evidence\": \"GSK3β inhibitors and RNAi, BCL10 phosphorylation and MALT1 substrate-cleavage assays\",\n      \"pmids\": [\"29358699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation sites not precisely mapped\", \"Single-lab, largely pharmacological\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the physiological importance of CBM/MALT1 protease activity for regulatory T cell suppressive function, showing acute BCL10 loss in mature Tregs causes lethal autoimmunity.\",\n      \"evidence\": \"Conditional Bcl10 knockout in Tregs, suppression and colitis-transfer assays, MALT1 inhibitor validation\",\n      \"pmids\": [\"31138793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BCL10-dependent transcriptional targets governing suppression not fully mapped\", \"Does not address BCL10 in conventional T cell tolerance\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected BCL10 biology to disease by defining two biochemically distinct oncogenic BCL10 mutation classes in ABC-DLBCL — filament-stabilizing CARD missense and MALT1-disinhibiting C-terminal truncations — with divergent BTK- and MALT1-inhibitor sensitivities.\",\n      \"evidence\": \"Structural analysis, polymerization and MALT1 activity assays, drug-sensitivity testing in primary lymphoma and cell lines\",\n      \"pmids\": [\"35658124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency and prognostic impact across patient cohorts not addressed here\", \"Resistance mechanisms beyond these two classes unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple competing phosphorylation, ubiquitination, dephosphorylation, and degradation inputs are temporally integrated on the BCL10 filament to set NF-κB amplitude and duration, and what structurally distinguishes BCL10's NF-κB scaffolding from its actin/membrane-remodeling function, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model coupling filament dynamics to PTM cycles\", \"Structural basis of the NF-κB-independent AP1/EpsinR/OCRL function undetermined\", \"Direct E3 ligases for each BCL10 ubiquitin chain type not all assigned\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 9, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 8, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 27, 34]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [36, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 13, 25, 42]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 14, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [43]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"complexes\": [\"CBM signalosome (CARMA1/CARD11-BCL10-MALT1)\", \"p62-BCL10-MALT1-IKK signalosome\", \"BCL10-AP1/EpsinR complex\"],\n    \"partners\": [\"MALT1\", \"CARD11\", \"CARD9\", \"TRAF6\", \"IKBKG\", \"SQSTM1\", \"RIPK2\", \"AKT1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}