{"gene":"CARD11","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2001,"finding":"CARD11 (CARMA1) is a CARD-containing MAGUK family scaffolding protein whose CARD domain associates specifically with the CARD domain of BCL10, and when expressed in cells induces NF-κB activation and BCL10 phosphorylation.","method":"Co-immunoprecipitation, domain mapping, cell transfection NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional reporter assay, replicated across multiple early papers","pmids":["11278692"],"is_preprint":false},{"year":2001,"finding":"CARMA1 binds BCL10 via CARD-CARD interaction, induces translocation of BCL10 from cytoplasm to perinuclear structures, and stimulates BCL10 phosphorylation and NF-κB activation.","method":"Co-immunoprecipitation, confocal microscopy, overexpression in cells","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; replicated by multiple labs","pmids":["11356195"],"is_preprint":false},{"year":2002,"finding":"CARD11 mediates NF-κB activation selectively downstream of TCR/CD28 (but not TNFα or dsRNA), functions upstream of the IKK complex, and requires its CARD domain to cooperate with BCL10; CARD, coiled-coil, SH3, and GUK domains are each critical for signaling.","method":"Expression cloning, RNAi knockdown, RNAi-rescue domain mutagenesis, NF-κB reporter assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — expression cloning plus domain mutagenesis with functional rescue","pmids":["12356734"],"is_preprint":false},{"year":2002,"finding":"CARMA1 is constitutively associated with lipid rafts; TCR stimulation induces physical association of CARMA1 with TCR and BCL10, and BCL10 translocates into lipid rafts upon TCR engagement. A CARMA1 mutant defective for BCL10 binding acts as dominant-negative for TCR-induced NF-κB and JNK activation.","method":"Co-immunoprecipitation, lipid raft fractionation, dominant-negative transfection, cytokine assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus fractionation plus functional dominant-negative, replicated","pmids":["12154360"],"is_preprint":false},{"year":2002,"finding":"CARMA1 deficiency selectively impairs TCR-induced NF-κB activation and IL-2 production; reconstitution of CARMA1-deficient T cells with CARMA1 fully rescues the signaling defect.","method":"Somatic mutagenesis screen, reconstitution assay, NF-κB reporter, cytokine ELISA","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function cell line with reconstitution rescue","pmids":["12154356"],"is_preprint":false},{"year":2003,"finding":"Genetic inactivation of CARD11 in mice causes a complete block in T and B cell immunity with a selective defect in JNK and NF-κB activation downstream of antigen receptors and PKC; CARD11 is also required for TLR4/LPS-induced B cell proliferation and JNK activation.","method":"Genetic knockout mouse, proliferation assay, cytokine production, kinase activation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and biochemical phenotype, replicated across multiple KO papers","pmids":["12818158"],"is_preprint":false},{"year":2003,"finding":"A point mutation (L232R equivalent) in the CARD11 coiled-coil domain abolishes antigen receptor-specific NF-κB and JNK signaling while preserving calcium/NFAT/ERK signaling, identifying the coiled-coil domain as essential for pathway-specific signaling.","method":"ENU forward genetic screen, reconstitution/complementation, signaling assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic screen with biochemical pathway dissection","pmids":["12818157"],"is_preprint":false},{"year":2003,"finding":"CARMA1 is required for recruitment of BCL10 to clustered TCR complexes and lipid rafts; its CARD domain is essential for engaging downstream signaling components in vivo.","method":"Knockout mouse, CARD-deleted knock-in mouse, lipid raft fractionation, NF-κB and proliferation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — two genetic models (KO and knock-in) with orthogonal biochemical and cellular readouts","pmids":["12867038","12867037"],"is_preprint":false},{"year":2004,"finding":"CARMA1 membrane association (via its MAGUK domain) is essential for function; CARMA1 recruits PKCθ, BCL10, and IKKβ into lipid rafts at the immunological synapse in a signal-dependent manner; BCL10-CARD fusion restores signaling in CARMA1-deficient cells lacking CARD.","method":"Reconstitution of CARMA1-deficient T cells, lipid raft fractionation, immunofluorescence, NF-κB reporter","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis with reconstitution, multiple orthogonal readouts","pmids":["14673152"],"is_preprint":false},{"year":2004,"finding":"CARMA1 controls entry of IKK into lipid raft aggregates and the central region (cSMAC) of the immune synapse downstream of PKC, without affecting overall synapse organization or TCR/LFA-1/PKCθ recruitment to the synapse.","method":"Knockout T cells, peptide-specific imaging system, lipid raft fractionation, IKK activity assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with live-cell imaging and biochemical fractionation","pmids":["15520247"],"is_preprint":false},{"year":2004,"finding":"MALT1 is recruited to lipid rafts of the immunological synapse downstream of CARMA1 (CARMA1-deficient cells fail to recruit MALT1); MALT1 associates with CARMA1 in a BCL10-independent manner, and MALT1/BCL10/CARMA1 form a trimolecular complex.","method":"Lipid raft fractionation, Co-immunoprecipitation in CARMA1-deficient and reconstituted cells, dominant-negative deletion mutant assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic CARMA1-deficient cells plus reciprocal Co-IP, BCL10-independent CARMA1-MALT1 interaction demonstrated","pmids":["14754896"],"is_preprint":false},{"year":2004,"finding":"CARMA1 physically associates with IKKγ/NEMO and participates in an inducible large complex containing IKKγ/NEMO, BCL10, and IKKα/β; expression of the NEMO-binding region of CARMA3 exerts dominant-negative effects on BCL10-mediated NF-κB activation.","method":"Co-immunoprecipitation, dominant-negative overexpression, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP interaction demonstrated plus dominant-negative, single lab","pmids":["15184390"],"is_preprint":false},{"year":2005,"finding":"BCR engagement induces progressive recruitment of CARMA1 into lipid rafts and association with PKCβ, which phosphorylates CARMA1 at S564, S649, and S657 in the serine-rich linker domain; mutation of S564 and S657 ablates CARMA1 function, whereas deletion of the linker causes constitutive, PKC-independent NF-κB activation.","method":"Lipid raft fractionation, in vitro kinase assay, site-directed mutagenesis, NF-κB reporter assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus mutagenesis plus functional reporter, replicated by parallel paper","pmids":["16356855"],"is_preprint":false},{"year":2005,"finding":"PKCθ phosphorylates CARMA1 in vitro and in vivo at Ser552 (linker region) following TCR-CD28 costimulation; CARMA1 S552A mutant fails to mediate TCR-induced NF-κB activation in CARMA1-deficient T cells and fails to recruit downstream signaling components to the immunological synapse.","method":"In vitro kinase assay, phospho-specific antibody, site-directed mutagenesis, reconstitution of CARMA1-deficient T cells, immunological synapse imaging","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus mutagenesis plus cellular reconstitution with imaging","pmids":["16356856"],"is_preprint":false},{"year":2005,"finding":"TAK1 is required for IKK activation in BCR signaling and interacts with phosphorylated CARMA1; this interaction is mediated by PKCβ. IKK is also recruited to the CARMA1-BCL10-MALT1 complex in a PKCβ-dependent manner.","method":"Co-immunoprecipitation, kinase assay, siRNA knockdown, PKCβ-deficient B cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with genetic (PKCβ-KO) and siRNA tools in multiple cell systems","pmids":["16301747"],"is_preprint":false},{"year":2006,"finding":"IKKβ is required for initial CBM complex formation; upon engagement with the Carma1/BCL10/MALT1 complex, IKKβ phosphorylates BCL10 at its C-terminus, disrupting BCL10-MALT1 association and BCL10-mediated IKKγ ubiquitination — a negative regulatory feedback step.","method":"Genetic IKKβ-deficient T cells, in vitro kinase assay, mutagenesis of BCL10 phosphorylation sites, co-immunoprecipitation, cytokine measurement","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus genetic model plus mutagenesis, multiple orthogonal methods","pmids":["16818229"],"is_preprint":false},{"year":2006,"finding":"CaMKII is redistributed to the immune synapse upon T cell activation, phosphorylates CARMA1 on Ser109, and this phosphorylation facilitates the CARMA1-BCL10 interaction to enhance NF-κB activation.","method":"Computational expression analysis, CaMKII inhibitor/siRNA, in vitro kinase assay, Co-immunoprecipitation, NF-κB reporter","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay plus Co-IP plus functional assay; single lab","pmids":["16809782"],"is_preprint":false},{"year":2006,"finding":"CARMA1 selectively regulates JNK2 (not JNK1) downstream of TCR signaling; BCL10 is inducibly associated with JNK2 and acts as a JIP-like scaffold assembling JNK2, MKK7, and TAK1; this CARMA1/BCL10-JNK2 axis controls c-Jun protein levels.","method":"Genetic KO mice for CARMA1/BCL10, Co-immunoprecipitation, JNK isoform-specific kinase assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with Co-IP and isoform-specific kinase assays, selective JNK2 regulation demonstrated","pmids":["17189706"],"is_preprint":false},{"year":2007,"finding":"CARMA1 undergoes K48-linked polyubiquitination and proteasome-dependent degradation upon antigen receptor activation; ubiquitin acceptor sites reside in the SH3 and GUK domains; deletion of the Hook domain between SH3 and GUK induces constitutive ubiquitination; elimination of ubiquitination sites elevates NF-κB and JNK activation.","method":"Site-directed mutagenesis, proteasome inhibitor treatment, ubiquitin linkage-specific antibodies, NF-κB reporter, JNK assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis plus pharmacological inhibition plus linkage-specific antibodies","pmids":["20008554"],"is_preprint":false},{"year":2007,"finding":"IKKβ contributes to formation of the CARMA1-BCL10-MALT1 complex in B cells by phosphorylating CARMA1 (in addition to PKCβ-mediated phosphorylation at Ser668); PKCβ-mediated Ser668 phosphorylation is essential for BCR-induced CBM association and subsequent IKK activation.","method":"Phospho-specific antibodies, PKCβ-deficient B cells, IKKβ inhibitor, Co-immunoprecipitation, kinase assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — phospho-specific antibodies plus genetic PKCβ-KO plus inhibitor, multiple orthogonal methods","pmids":["18086859"],"is_preprint":false},{"year":2007,"finding":"Caveolin-1 ligation of CD26 induces T cell NF-κB activation; the cytoplasmic tail of CD26 interacts with CARMA1, recruiting a complex of CD26/CARMA1/BCL10/IKK to lipid rafts.","method":"Co-immunoprecipitation, lipid raft fractionation, NF-κB reporter, soluble caveolin-1-Fc fusion protein stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus functional reporter, single lab","pmids":["17287217"],"is_preprint":false},{"year":2007,"finding":"CARMA1 coiled-coil domain mediates constitutive oligomerization of CARMA1; disruption of coiled-coil structure impairs oligomerization and abrogates NF-κB activation; the CC1 subdomain is required for CARMA1 subcellular localization and CC2 for self-association.","method":"Co-immunoprecipitation of CARMA1 with itself, coiled-coil mutagenesis, subcellular localization imaging, NF-κB reporter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — mutagenesis with localization and functional readouts; single lab","pmids":["17428801"],"is_preprint":false},{"year":2008,"finding":"CARD11 contains a PKC-responsive inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors (BCL10, TRAF6, TAK1, IKKγ, caspase-8) through intramolecular interactions requiring both CARD and coiled-coil domains; TRAF6 and caspase-8 associate with CARD11 in a signal-inducible manner; CARD11 can recruit cofactors independently of BCL10 or MALT1.","method":"Domain mutagenesis, RNAi rescue assay, Co-immunoprecipitation in BCL10/MALT1-deficient cells, NF-κB reporter","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — extensive domain mutagenesis, RNAi rescue, genetic-deficient cells, multiple cofactors tested","pmids":["18625728"],"is_preprint":false},{"year":2008,"finding":"Oncogenic CARD11 coiled-coil domain mutations (e.g., L225LI) found in ABC-DLBCL induce constitutive NF-κB activation and enhance NF-κB activity upon antigen receptor stimulation when introduced into lymphoma cell lines.","method":"Sanger sequencing of DLBCL biopsies, transfection of mutant constructs into lymphoma cell lines, NF-κB reporter assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — systematic mutation identification plus functional cell-based validation, landmark paper","pmids":["18323416"],"is_preprint":false},{"year":2009,"finding":"Cbl-b E3 ligase monoubiquitinates CARMA1, which disrupts CARMA1-BCL10 complex formation (without affecting CARMA1 protein stability), thereby suppressing NF-κB activation during NKT cell anergy.","method":"Co-immunoprecipitation, ubiquitination assay, Cbl-b KO mice, CARMA1 KO NKT cells, IFN-γ production","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus in vivo ubiquitination assay plus Co-IP, mechanistic link established","pmids":["19815501"],"is_preprint":false},{"year":2009,"finding":"PP2A (regulatory subunit Aα/PPP2R1A) interacts with CARMA1 and dephosphorylates PKCθ-dependent Ser645 phosphorylation on CARMA1; maintenance of this phosphorylation correlates with increased CBM complex formation, NF-κB activation, and IL-2/IFN-γ production.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro dephosphorylation assay, phospho-specific antibodies, cytokine assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro dephosphorylation plus genetic siRNA plus phospho-specific antibodies","pmids":["21157432"],"is_preprint":false},{"year":2009,"finding":"HPK1 kinase interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the CARMA1 linker region at residues S549, S551, and S552 (distinct from PKC sites); CARMA1 S551A or S549A/S551A mutants fail to restore HPK1-mediated NF-κB activation in CARMA1-deficient T cells.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, reconstitution of CARMA1-deficient cells, NF-κB reporter","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus mutagenesis plus genetic reconstitution","pmids":["19706536"],"is_preprint":false},{"year":2009,"finding":"CARMA1 serine 649 phosphorylation, occurring later and more persistently than S657 phosphorylation after antigen receptor stimulation, down-regulates CARMA1 activity; S649A mutation promotes enhanced IKK and JNK activation at low stimulation doses.","method":"Phospho-specific antibodies, site-directed mutagenesis, PKCβ-deficient B cells, DT40 CARMA1-deficient reconstitution, IKK/JNK assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — phospho-specific antibodies plus mutagenesis plus genetic reconstitution, temporal kinetics resolved","pmids":["19917688"],"is_preprint":false},{"year":2010,"finding":"Oncogenic CARD11 mutations F123I and L225LI induce hyperactivity by disrupting autoinhibition by the CARD11 inhibitory domain (ID): they disrupt ID-mediated intramolecular interactions, bypass the requirement for ID phosphorylation during TCR signaling, and selectively enhance CARD11 affinity for BCL10.","method":"Co-immunoprecipitation, mutagenesis, dominant-negative ID peptide, phosphorylation-mimetic/defective mutants, NF-κB reporter","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — domain mutagenesis plus intramolecular interaction assays with multiple oncogenic mutations tested","pmids":["20799731"],"is_preprint":false},{"year":2010,"finding":"Calcineurin (activated by calcium) positively regulates CBM complex formation by dephosphorylating BCL10, promoting CARMA1-BCL10-MALT1 assembly; calcineurin A is physically associated with the CBM complex.","method":"Cyclosporin A/FK506 pharmacological inhibition, EGTA-AM calcium chelation, calcineurin siRNA knockdown, in vitro dephosphorylation, Co-immunoprecipitation, NF-κB reporter","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro dephosphorylation plus multiple pharmacological/genetic tools plus Co-IP","pmids":["21199863"],"is_preprint":false},{"year":2011,"finding":"OX40 (a TNFR family member) assembles a signalosome containing TRAF2, RIP, IKKα/β/γ as well as CARMA1, MALT1, BCL10, and PKC in membrane microdomains independently of TCR engagement; NF-κB activation by OX40 requires CARMA1 and PKC.","method":"Co-immunoprecipitation, membrane microdomain fractionation, genetic-deficient cells, NF-κB reporter, T cell survival assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus fractionation plus functional analysis; single lab","pmids":["21282629"],"is_preprint":false},{"year":2011,"finding":"ADAP associates with CARMA1 and is required for TCR-stimulated assembly of the CARMA1-BCL10-MALT1 complex; a distinct region of ADAP mediates CARMA1 association and NF-κB activation, separable from ADAP's role in adhesion regulation.","method":"ADAP-deficient T cells, Co-immunoprecipitation, NF-κB nuclear translocation assay, IκBα phosphorylation/degradation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — genetic ADAP-deficient cells plus Co-IP plus domain separation study","pmids":["17478723"],"is_preprint":false},{"year":2013,"finding":"The reconstituted CBM signalosome forms a helical filamentous assembly in which substoichiometric CARMA1 nucleates BCL10 CARD filaments in a highly cooperative process; crystallography, NMR, and EM reveal the Bcl10 CARD filament structure and CARMA1-BCL10 interface; structure-guided mutagenesis confirmed these interfaces for MALT1 activation in vitro and NF-κB activation in cells.","method":"In vitro reconstitution, cryo-EM, X-ray crystallography, NMR, electron microscopy, site-directed mutagenesis, NF-κB reporter","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — reconstitution plus structure (crystallography, NMR, EM) plus mutagenesis validation in vitro and in cells","pmids":["24074955"],"is_preprint":false},{"year":2013,"finding":"USP9X deubiquitinating enzyme interacts with BCL10 in the CBM complex and removes TCR-induced ubiquitin chains from BCL10, which facilitates CARMA1-BCL10-MALT1 association and is required for NF-κB activation in T cells.","method":"Co-immunoprecipitation, USP9X siRNA knockdown, ubiquitination assay, NF-κB reporter, T cell proliferation/cytokine assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus siRNA knockdown plus ubiquitination assay; single lab","pmids":["23690623"],"is_preprint":false},{"year":2013,"finding":"STUB1 (an E3 ubiquitin ligase) constitutively interacts with CARMA1 and catalyzes Lys-27-linked ubiquitination of CARMA1 upon TCR stimulation; STUB1 knockdown diminishes TCR-induced NF-κB activation and IL-2 production.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay with linkage-specific mutant ubiquitin, NF-κB reporter, cytokine assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus K27-specific ubiquitination assay plus siRNA functional readout; single lab","pmids":["23322406"],"is_preprint":false},{"year":2014,"finding":"CARMA1 (and MALT1 but not BCL10) is required for optimal TCR/CD28-induced mTORC1 activation in T cells; MALT1 catalytic activity is required for CD4+ T cell proliferation and increased metabolic flux in activated T cells.","method":"Genetic-deficient cells, MALT1 catalytic inhibitor, mTOR substrate phosphorylation assay, metabolic flux assay, T cell proliferation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — genetic CBM component-deficient cells plus pharmacological MALT1 inhibition plus multiple metabolic readouts","pmids":["24917592"],"is_preprint":false},{"year":2015,"finding":"CARMA1 clustering through SH3-GUK domain interactions (intra- and intermolecular) is required for activation-induced microcluster formation at the immunological synapse and for TCR-induced and oncogenic NF-κB signaling; disruption of SH3-GUK interactions abolishes CARMA1 microclusters and NF-κB activation.","method":"SH3/GUK mutagenesis, live-cell confocal imaging of synapse microclusters, Co-immunoprecipitation, NF-κB reporter, ABC-DLBCL cell lines","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis plus live-cell imaging plus functional reporter, mechanistic link established","pmids":["25602919"],"is_preprint":false},{"year":2015,"finding":"RNF181, an E3 ubiquitin ligase identified by BRIC screening, interacts with CARD11 and ubiquitinates BCL10 to negatively regulate antigen receptor signaling to NF-κB; RNF181 limits DLBCL cell proliferation dependent on aberrant CARD11 signaling.","method":"BRIC interaction screen, Co-immunoprecipitation, in vitro ubiquitination assay, BCL10 protein level assay, NF-κB reporter, DLBCL cell proliferation assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vitro ubiquitination assay plus Co-IP plus functional cell proliferation; single lab","pmids":["26711259"],"is_preprint":false},{"year":2016,"finding":"BCL10 undergoes TCR-induced linear (LUBAC/HOIP-mediated) polyubiquitination, which is required for association with NEMO/IKKγ; CARD11 promotes this by co-recruiting BCL10 and HOIP via its coiled-coil domain; oncogenic CARD11 variants spontaneously induce Lin(Ub)n-BCL10 correlating with enhanced HOIP and BCL10 binding.","method":"Linear ubiquitin-specific antibodies, site-directed mutagenesis of BCL10 lysines, HOIP/CARD11 domain mutagenesis, Co-immunoprecipitation, NF-κB reporter","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — linkage-specific ubiquitin detection plus mutagenesis plus Co-IP, mechanistic framework clearly established","pmids":["27777308"],"is_preprint":false},{"year":2016,"finding":"The CARD11 inhibitory domain (ID) contains four repressive elements (REs) that function cooperatively and redundantly to prevent spontaneous NF-κB activation; each RE contributes to closed inactive state maintenance and prevention of BCL10 binding; oncogenic mutations disrupt intramolecular interactions mediated by multiple REs.","method":"Domain mutagenesis, intramolecular interaction assay, quantitative NF-κB reporter assay, domain-deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — systematic mutagenesis of four REs with quantitative signaling output plus intramolecular interaction assay","pmids":["26884334","26884335"],"is_preprint":false},{"year":2017,"finding":"Germline hypomorphic CARD11 mutations cause loss-of-function and dominant-interfering activity for antigen receptor-induced NF-κB and mTORC1 signaling; glutamine supplementation partially rescues mTORC1 and IFN-γ production defects, indicating CARD11 is required for glutamine import into T cells.","method":"Transfection of mutant constructs, NF-κB and mTORC1 reporter assays, patient primary T cell functional assays, glutamine supplementation rescue experiment","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in both cell lines and patient primary cells, metabolic rescue experiment","pmids":["28628108"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of BCL10 CARD filament at 4.0 Å redefines CARD-CARD interactions; BCL10 polymerizes in a unidirectional manner in time-lapse confocal imaging; CARMA1 serves as a hub nucleating star-shaped BCL10 filament networks and decreases the lag period of BCL10 polymerization; MALT1 immediately dimerizes on BCL10 filaments and TRAF6 cooperatively decorates CBM filaments in higher-order assemblies.","method":"Cryo-EM structure determination, time-lapse confocal imaging, in vitro polymerization assay, EM of MALT1/TRAF6 decoration","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure plus live-cell imaging plus in vitro reconstitution, single rigorous study","pmids":["29382759"],"is_preprint":false},{"year":2019,"finding":"Structure of a CARD9 region containing an extensive CARD-coiled-coil interface reveals the structural basis for autoinhibition; disruption of this interface leads to hyperactivation and Bcl10-templating filament formation in vitro for both CARD9 and CARD11; structure of the CARD9 filament illuminates mechanisms of CARD11 oncogenic mutations and how autoinhibition is relieved during canonical activation.","method":"X-ray crystallography of autoinhibited CARD9, cryo-EM of CARD9 filament, cell-based hyperactivation assays, in vitro filament polymerization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus cryo-EM plus in vitro reconstitution plus cell-based mutagenesis","pmids":["31296852"],"is_preprint":false},{"year":2010,"finding":"GAKIN (a kinesin-3 family member) associates with CARD11 in a signal-dependent manner, competes with BCL10 for CARD11 association, and dynamically localizes to the immunological synapse to redistribute CARD11 from the central to a distal region, thereby negatively regulating TCR signaling to NF-κB.","method":"Expression-cloning screen, Co-immunoprecipitation, live-cell imaging at immunological synapse, NF-κB reporter, competition binding assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — expression cloning plus Co-IP plus live-cell imaging plus functional NF-κB assay","pmids":["21145487"],"is_preprint":false},{"year":2012,"finding":"A quantitative signaling screen identifies gain-of-function CARD11 mutations in the CARD and LATCH domains; LATCH domain functions with the CARD to promote autoinhibition; mutations in LATCH or CARD disrupt inhibitory domain binding, promote BCL10 association, induce BCL10 ubiquitination, NF-κB activation, and human lymphoma cell survival.","method":"High-throughput quantitative NF-κB signaling screen, domain mutagenesis, Co-immunoprecipitation, ubiquitination assay, lymphoma cell survival assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — unbiased quantitative screen plus mutagenesis plus Co-IP plus functional cell survival assay","pmids":["23149938"],"is_preprint":false},{"year":2021,"finding":"Complete human CARD11 deficiency (biallelic p.Arg837* loss-of-function) prevents CBM complex formation, severely impairs NF-κB, JNK, and MALT1 paracaspase activation in B and T cells, and causes a developmental block in B cells at the naive/type 1 transitional stage with impaired T follicular helper cell development.","method":"Whole-exome sequencing, immunoblot signaling assays, flow cytometry immunophenotyping, MALT1 paracaspase activity assay, transcriptomics, hematopoietic stem cell transplantation functional restoration","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical and cellular assays in patient cells with functional restoration by HSCT","pmids":["33872653"],"is_preprint":false}],"current_model":"CARD11 (CARMA1) is a lymphocyte-specific CARD-MAGUK scaffold protein that is held in a closed, autoinhibited state by an inhibitory domain (containing four repressive elements and requiring CARD-coiled-coil intramolecular contacts); upon antigen receptor stimulation, PKCβ/θ (and additional kinases HPK1, CaMKII) phosphorylate CARD11's linker/inhibitory domain, relieving autoinhibition and allowing CARD11 to oligomerize, recruit to lipid rafts and the immunological synapse, and nucleate BCL10 CARD filaments through CARD-CARD interactions, which in turn recruit MALT1 (forming the CBM signalosome) that activates TRAF6/TAK1/IKK for canonical NF-κB and JNK2/AP-1 signaling, as well as mTORC1 activation and LUBAC-mediated linear ubiquitination of BCL10-NEMO; negative regulation is achieved by PP2A dephosphorylation of CARD11, K48-polyubiquitination and proteasomal degradation via its SH3-GUK MAGUK domain, Cbl-b monoubiquitination, and GAKIN-mediated displacement from the synapse, while oncogenic gain-of-function mutations in the coiled-coil, CARD, or LATCH domains disrupt autoinhibition to drive constitutive NF-κB activation in lymphomas, and germline loss-of-function mutations cause combined immunodeficiency."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of CARD11 as a CARD-MAGUK scaffold that binds BCL10 via CARD-CARD interactions and activates NF-κB established the founding molecular connection between a MAGUK-family protein and the NF-κB pathway in lymphocytes.","evidence":"Co-immunoprecipitation, domain mapping, NF-κB reporter assays, and confocal microscopy in transfected cells","pmids":["11278692","11356195"],"confidence":"High","gaps":["Physiological stimuli activating CARD11 were not yet identified","Mechanism of BCL10 phosphorylation downstream of CARD11 unknown"]},{"year":2002,"claim":"Demonstration that CARD11 selectively mediates antigen receptor (TCR/BCR)–induced but not TNFα-induced NF-κB and JNK signaling, acting upstream of IKK in lipid rafts, defined its pathway specificity and placed it at the apex of adaptive immune NF-κB signaling.","evidence":"RNAi knockdown, reconstitution with domain mutants, lipid raft fractionation, somatic mutagenesis screen, and dominant-negative approaches in T cells","pmids":["12356734","12154360","12154356"],"confidence":"High","gaps":["The activating kinase upstream of CARD11 was not identified","How CARD11 associates with lipid rafts was unclear"]},{"year":2003,"claim":"Genetic knockout of CARD11 in mice confirmed it is essential for T and B cell immunity, NF-κB/JNK activation downstream of antigen receptors, and identified the coiled-coil domain as a critical structural determinant for pathway-specific signaling.","evidence":"CARD11 knockout mice, ENU forward genetic screen, CARD-deleted knock-in mice, proliferation and cytokine assays","pmids":["12818158","12818157","12867038"],"confidence":"High","gaps":["The molecular mechanism by which the coiled-coil domain contributes to signaling was unknown","Whether CARD11 signals independently of BCL10 was unresolved"]},{"year":2004,"claim":"CARD11 was shown to orchestrate a trimolecular CBM signalosome by recruiting BCL10, MALT1, PKCθ, and IKK into lipid raft aggregates at the immunological synapse, with MALT1 associating with CARD11 independently of BCL10.","evidence":"Reconstitution of CARD11-deficient T cells, lipid raft fractionation, live-cell synapse imaging, Co-immunoprecipitation in BCL10-deficient backgrounds","pmids":["14673152","15520247","14754896","15184390"],"confidence":"High","gaps":["The activating phosphorylation events on CARD11 were not yet mapped","Stoichiometry of the CBM complex was unknown"]},{"year":2005,"claim":"PKCβ and PKCθ were identified as the direct activating kinases that phosphorylate CARD11's linker region (S552/S564/S649/S657/S668), and deletion of the linker was found to cause constitutive NF-κB activation, revealing a phosphorylation-regulated autoinhibitory switch.","evidence":"In vitro kinase assays, phospho-specific antibodies, site-directed mutagenesis, reconstitution of CARD11-deficient T and B cells, synapse imaging","pmids":["16356855","16356856"],"confidence":"High","gaps":["Additional kinases contributing to CARD11 activation were not yet known","Structural basis of autoinhibition was unresolved"]},{"year":2006,"claim":"CaMKII was identified as an additional CARD11 kinase (Ser109), and CARD11 was shown to selectively regulate JNK2 via a BCL10-scaffolded MKK7/TAK1 module, broadening the effector outputs of the CBM complex beyond NF-κB.","evidence":"CaMKII inhibitor/siRNA, in vitro kinase assay, JNK isoform-specific kinase assays in CARMA1/BCL10 KO mice","pmids":["16809782","17189706"],"confidence":"High","gaps":["Physiological importance of CaMKII phosphorylation relative to PKC was unclear","How JNK2 selectivity is achieved structurally was unknown"]},{"year":2007,"claim":"ADAP was shown to associate with CARMA1 and promote CBM assembly, while CARD11's coiled-coil domain was demonstrated to mediate constitutive self-oligomerization required for NF-κB activation, revealing both an upstream adaptor input and the oligomerization mechanism.","evidence":"ADAP-deficient T cells, Co-immunoprecipitation, coiled-coil mutagenesis, subcellular localization imaging","pmids":["17478723","17428801"],"confidence":"High","gaps":["How ADAP-CARD11 interaction is regulated was unknown","Whether oligomerization suffices for activation or requires additional signals was unresolved"]},{"year":2008,"claim":"Discovery of the inhibitory domain (ID) as a PKC-responsive switch that controls CARD11 association with multiple cofactors (BCL10, TRAF6, TAK1, NEMO, caspase-8) through intramolecular CARD-coiled-coil contacts established the autoinhibition model, while oncogenic coiled-coil mutations in ABC-DLBCL were shown to constitutively activate NF-κB by disrupting this mechanism.","evidence":"Extensive domain mutagenesis in BCL10/MALT1-deficient cells, RNAi rescue, sequencing of DLBCL biopsies with functional validation in lymphoma lines","pmids":["18625728","18323416"],"confidence":"High","gaps":["Number and identity of repressive elements within the ID were not mapped","Structural basis of oncogenic mutation hyperactivity was unknown"]},{"year":2009,"claim":"Multiple negative regulatory mechanisms were identified: PP2A dephosphorylates PKCθ-dependent CARD11 Ser645 to terminate signaling, Cbl-b monoubiquitinates CARD11 to disrupt BCL10 binding during NKT anergy, and HPK1 phosphorylates distinct linker residues to modulate activation, revealing that CARD11 integrates opposing phosphorylation/ubiquitination signals.","evidence":"In vitro dephosphorylation, phospho-specific antibodies, siRNA, Cbl-b/CARMA1 KO mice, HPK1 in vitro kinase assay with mutagenesis, reconstitution","pmids":["21157432","19815501","19706536","19917688"],"confidence":"High","gaps":["Temporal coordination of these opposing modifications was not fully resolved","Whether PP2A and Cbl-b act on the same or distinct pools of CARD11 was unknown"]},{"year":2010,"claim":"GAKIN kinesin was identified as a signal-dependent negative regulator that competes with BCL10 for CARD11 binding and physically displaces CARD11 from the central synapse, while oncogenic mutations were shown to bypass ID autoinhibition by disrupting intramolecular interactions.","evidence":"Expression-cloning screen, live-cell synapse imaging, competition binding assay, Co-immunoprecipitation, phosphorylation-mimetic mutants","pmids":["21145487","20799731"],"confidence":"High","gaps":["Motor activity requirement for GAKIN's negative regulation was not tested","How oncogenic mutations alter CARD11 conformational dynamics structurally was unknown"]},{"year":2012,"claim":"A quantitative signaling screen identified gain-of-function mutations in the CARD and LATCH domains, establishing that the LATCH cooperates with the CARD to maintain autoinhibition, and that disruption of either promotes BCL10 association, ubiquitination, and lymphoma cell survival.","evidence":"High-throughput NF-κB signaling screen, domain mutagenesis, Co-immunoprecipitation, lymphoma cell survival assay","pmids":["23149938"],"confidence":"High","gaps":["Structural definition of the LATCH domain was lacking","Precise intramolecular contacts between LATCH and ID were not mapped"]},{"year":2013,"claim":"Structural reconstitution revealed that CARD11 nucleates cooperative BCL10 CARD filament polymerization in a helical assembly, providing the first structural framework for how substoichiometric CARD11 amplifies downstream signaling through a prion-like templating mechanism.","evidence":"Cryo-EM, X-ray crystallography, NMR of BCL10 CARD filament, in vitro reconstitution, structure-guided mutagenesis validated in cells","pmids":["24074955"],"confidence":"High","gaps":["Full-length CARD11 structure was not determined","Stoichiometry of CARD11 within native signalosomes in cells was unknown"]},{"year":2014,"claim":"CARD11 was shown to be required for TCR/CD28-induced mTORC1 activation, linking the CBM signalosome to metabolic reprogramming beyond NF-κB.","evidence":"Genetic CARD11-deficient cells, mTOR substrate phosphorylation assay, MALT1 catalytic inhibitor, metabolic flux measurement","pmids":["24917592"],"confidence":"High","gaps":["Molecular mechanism connecting CBM to mTORC1 was not identified","Whether CARD11 regulates amino acid transport directly was unknown"]},{"year":2016,"claim":"The ID was dissected into four cooperatively acting repressive elements, and CARD11 was shown to promote LUBAC/HOIP-mediated linear ubiquitination of BCL10 for NEMO recruitment via its coiled-coil domain, completing the picture of how CARD11 coordinates both activation and ubiquitin-dependent signaling outputs.","evidence":"Systematic RE mutagenesis with quantitative NF-κB readout, linear ubiquitin-specific antibodies, HOIP/CARD11 coiled-coil domain mutagenesis, Co-IP","pmids":["26884334","26884335","27777308"],"confidence":"High","gaps":["Whether each RE has distinct regulatory inputs was not resolved","How LUBAC is recruited to CARD11 structurally was unknown"]},{"year":2018,"claim":"High-resolution cryo-EM of the BCL10 CARD filament and time-lapse imaging showed CARD11 acts as a hub nucleating star-shaped BCL10 filament networks, with MALT1 dimerizing immediately on filaments and TRAF6 cooperatively decorating them, providing an integrated structural model of the CBM signalosome.","evidence":"4.0 Å cryo-EM structure, time-lapse confocal imaging, in vitro polymerization, EM of MALT1/TRAF6 decoration","pmids":["29382759"],"confidence":"High","gaps":["Full-length activated CARD11 structure was still missing","In vivo filament dynamics and turnover were not characterized"]},{"year":2019,"claim":"Crystal structure of the CARD9 CARD–coiled-coil interface and cryo-EM of its filament provided a structural template for understanding CARD11 autoinhibition: disruption of the analogous CARD–coiled-coil interface in CARD11 leads to hyperactivation and spontaneous BCL10 filament templating.","evidence":"X-ray crystallography of autoinhibited CARD9, cryo-EM of CARD9 filament, cell-based CARD11 hyperactivation assays, in vitro filament polymerization","pmids":["31296852"],"confidence":"High","gaps":["Direct CARD11 CARD-coiled-coil structure was not determined","Conformational transition from autoinhibited to active CARD11 was not visualized"]},{"year":2021,"claim":"Complete human CARD11 deficiency was shown to cause combined immunodeficiency with impaired B cell development, absent NF-κB/JNK/MALT1 paracaspase activation, and defective T follicular helper cell generation, confirming CARD11 as an essential non-redundant node in human adaptive immunity.","evidence":"Whole-exome sequencing identifying biallelic p.Arg837* in patients, immunophenotyping, signaling assays in patient cells, functional restoration by HSCT","pmids":["33872653"],"confidence":"High","gaps":["Whether partial loss-of-function alleles produce a milder immunodeficiency spectrum was not fully characterized","Contribution of CARD11 to innate lymphoid cell function in humans was not assessed"]},{"year":null,"claim":"A high-resolution structure of full-length CARD11 in both autoinhibited and activated conformations, the precise mechanism linking CBM assembly to mTORC1 activation, and the in vivo dynamics of CARD11 filament formation and disassembly remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length CARD11 structure in either state","Mechanism connecting CBM to mTORC1/metabolic reprogramming is molecularly undefined","In vivo filament dynamics and stoichiometry at the synapse have not been measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,8,22,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,39,43]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8,9,12,36]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,7,13,45]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,17,35,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,44]}],"complexes":["CBM signalosome (CARD11-BCL10-MALT1)","CARD11-IKK complex"],"partners":["BCL10","MALT1","TRAF6","NEMO","PRKCB","PRKCQ","PPP2R1A","KIF13B"],"other_free_text":[]},"mechanistic_narrative":"CARD11 (CARMA1) is a lymphocyte-specific scaffold protein that couples antigen receptor and costimulatory signals to NF-κB, JNK2/AP-1, and mTORC1 activation. In its resting state, an intramolecular inhibitory domain (ID) containing four cooperatively acting repressive elements maintains CARD11 in a closed conformation through CARD–coiled-coil contacts; upon TCR or BCR engagement, PKCθ/PKCβ (and additional kinases HPK1 and CaMKII) phosphorylate the linker/ID region, relieving autoinhibition and enabling CARD11 oligomerization via coiled-coil and SH3-GUK domain interactions, recruitment to lipid raft microclusters at the immunological synapse, and nucleation of cooperative BCL10 CARD filaments that recruit MALT1 and TRAF6 into higher-order CBM signalosomes that activate the TAK1–IKK cascade and LUBAC-mediated linear ubiquitination of BCL10–NEMO [PMID:24074955, PMID:29382759, PMID:18625728, PMID:27777308, PMID:25602919]. Negative regulation is achieved by PP2A-mediated dephosphorylation, Cbl-b monoubiquitination disrupting BCL10 binding, K48-linked polyubiquitination and proteasomal degradation via the SH3-GUK domain, and GAKIN-mediated displacement from the synapse [PMID:21157432, PMID:19815501, PMID:20008554, PMID:21145487]. Gain-of-function mutations in the coiled-coil, CARD, or LATCH domains that disrupt autoinhibition drive constitutive NF-κB activation in diffuse large B-cell lymphoma, while biallelic loss-of-function mutations cause combined immunodeficiency with impaired B and T cell development [PMID:18323416, PMID:23149938, PMID:33872653]."},"prefetch_data":{"uniprot":{"accession":"Q9BXL7","full_name":"Caspase recruitment domain-containing protein 11","aliases":["CARD-containing MAGUK protein 1","Carma 1"],"length_aa":1154,"mass_kda":133.3,"function":"Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement (PubMed:11278692, PubMed:11356195, PubMed:12356734). Transduces signals downstream TCR or BCR activation via the formation of a multiprotein complex together with BCL10 and MALT1 that induces NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11356195). Upon activation in response to TCR or BCR triggering, CARD11 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to I-kappa-B kinase (IKK) phosphorylation and degradation, and release of NF-kappa-B proteins for nuclear translocation (PubMed:24074955). Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP (PubMed:27777308). Stimulates the phosphorylation of BCL10 (PubMed:11356195). Also activates the TORC1 signaling pathway (PubMed:28628108)","subcellular_location":"Cytoplasm; Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q9BXL7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CARD11","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CARD11","total_profiled":1310},"omim":[{"mim_id":"617638","title":"IMMUNODEFICIENCY 11B WITH ATOPIC DERMATITIS; IMD11B","url":"https://www.omim.org/entry/617638"},{"mim_id":"616452","title":"B-CELL EXPANSION WITH NFKB AND T-CELL ANERGY; BENTA","url":"https://www.omim.org/entry/616452"},{"mim_id":"616023","title":"SR-RELATED C-TERMINAL DOMAIN-ASSOCIATED FACTOR 4; SCAF4","url":"https://www.omim.org/entry/616023"},{"mim_id":"615468","title":"IMMUNODEFICIENCY 12; IMD12","url":"https://www.omim.org/entry/615468"},{"mim_id":"615206","title":"IMMUNODEFICIENCY 11A; IMD11A","url":"https://www.omim.org/entry/615206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":17.3},{"tissue":"lymphoid tissue","ntpm":37.8}],"url":"https://www.proteinatlas.org/search/CARD11"},"hgnc":{"alias_symbol":["CARMA1","BIMP3"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXL7","domains":[{"cath_id":"1.10.533.10","chopping":"12-92","consensus_level":"high","plddt":85.0323,"start":12,"end":92},{"cath_id":"2.30.30.40","chopping":"668-851","consensus_level":"medium","plddt":89.8185,"start":668,"end":851},{"cath_id":"3.40.50.300","chopping":"971-1152","consensus_level":"high","plddt":87.6395,"start":971,"end":1152}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXL7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXL7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXL7-F1-predicted_aligned_error_v6.png","plddt_mean":71.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CARD11","jax_strain_url":"https://www.jax.org/strain/search?query=CARD11"},"sequence":{"accession":"Q9BXL7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXL7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXL7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXL7"}},"corpus_meta":[{"pmid":"18323416","id":"PMC_18323416","title":"Oncogenic 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and when expressed in cells induces NF-κB activation and BCL10 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, cell transfection NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional reporter assay, replicated across multiple early papers\",\n      \"pmids\": [\"11278692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CARMA1 binds BCL10 via CARD-CARD interaction, induces translocation of BCL10 from cytoplasm to perinuclear structures, and stimulates BCL10 phosphorylation and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, overexpression in cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; replicated by multiple labs\",\n      \"pmids\": [\"11356195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CARD11 mediates NF-κB activation selectively downstream of TCR/CD28 (but not TNFα or dsRNA), functions upstream of the IKK complex, and requires its CARD domain to cooperate with BCL10; CARD, coiled-coil, SH3, and GUK domains are each critical for signaling.\",\n      \"method\": \"Expression cloning, RNAi knockdown, RNAi-rescue domain mutagenesis, NF-κB reporter assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — expression cloning plus domain mutagenesis with functional rescue\",\n      \"pmids\": [\"12356734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CARMA1 is constitutively associated with lipid rafts; TCR stimulation induces physical association of CARMA1 with TCR and BCL10, and BCL10 translocates into lipid rafts upon TCR engagement. A CARMA1 mutant defective for BCL10 binding acts as dominant-negative for TCR-induced NF-κB and JNK activation.\",\n      \"method\": \"Co-immunoprecipitation, lipid raft fractionation, dominant-negative transfection, cytokine assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus fractionation plus functional dominant-negative, replicated\",\n      \"pmids\": [\"12154360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CARMA1 deficiency selectively impairs TCR-induced NF-κB activation and IL-2 production; reconstitution of CARMA1-deficient T cells with CARMA1 fully rescues the signaling defect.\",\n      \"method\": \"Somatic mutagenesis screen, reconstitution assay, NF-κB reporter, cytokine ELISA\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function cell line with reconstitution rescue\",\n      \"pmids\": [\"12154356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic inactivation of CARD11 in mice causes a complete block in T and B cell immunity with a selective defect in JNK and NF-κB activation downstream of antigen receptors and PKC; CARD11 is also required for TLR4/LPS-induced B cell proliferation and JNK activation.\",\n      \"method\": \"Genetic knockout mouse, proliferation assay, cytokine production, kinase activation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and biochemical phenotype, replicated across multiple KO papers\",\n      \"pmids\": [\"12818158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A point mutation (L232R equivalent) in the CARD11 coiled-coil domain abolishes antigen receptor-specific NF-κB and JNK signaling while preserving calcium/NFAT/ERK signaling, identifying the coiled-coil domain as essential for pathway-specific signaling.\",\n      \"method\": \"ENU forward genetic screen, reconstitution/complementation, signaling assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic screen with biochemical pathway dissection\",\n      \"pmids\": [\"12818157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CARMA1 is required for recruitment of BCL10 to clustered TCR complexes and lipid rafts; its CARD domain is essential for engaging downstream signaling components in vivo.\",\n      \"method\": \"Knockout mouse, CARD-deleted knock-in mouse, lipid raft fractionation, NF-κB and proliferation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two genetic models (KO and knock-in) with orthogonal biochemical and cellular readouts\",\n      \"pmids\": [\"12867038\", \"12867037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA1 membrane association (via its MAGUK domain) is essential for function; CARMA1 recruits PKCθ, BCL10, and IKKβ into lipid rafts at the immunological synapse in a signal-dependent manner; BCL10-CARD fusion restores signaling in CARMA1-deficient cells lacking CARD.\",\n      \"method\": \"Reconstitution of CARMA1-deficient T cells, lipid raft fractionation, immunofluorescence, NF-κB reporter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with reconstitution, multiple orthogonal readouts\",\n      \"pmids\": [\"14673152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA1 controls entry of IKK into lipid raft aggregates and the central region (cSMAC) of the immune synapse downstream of PKC, without affecting overall synapse organization or TCR/LFA-1/PKCθ recruitment to the synapse.\",\n      \"method\": \"Knockout T cells, peptide-specific imaging system, lipid raft fractionation, IKK activity assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with live-cell imaging and biochemical fractionation\",\n      \"pmids\": [\"15520247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MALT1 is recruited to lipid rafts of the immunological synapse downstream of CARMA1 (CARMA1-deficient cells fail to recruit MALT1); MALT1 associates with CARMA1 in a BCL10-independent manner, and MALT1/BCL10/CARMA1 form a trimolecular complex.\",\n      \"method\": \"Lipid raft fractionation, Co-immunoprecipitation in CARMA1-deficient and reconstituted cells, dominant-negative deletion mutant assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic CARMA1-deficient cells plus reciprocal Co-IP, BCL10-independent CARMA1-MALT1 interaction demonstrated\",\n      \"pmids\": [\"14754896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CARMA1 physically associates with IKKγ/NEMO and participates in an inducible large complex containing IKKγ/NEMO, BCL10, and IKKα/β; expression of the NEMO-binding region of CARMA3 exerts dominant-negative effects on BCL10-mediated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP interaction demonstrated plus dominant-negative, single lab\",\n      \"pmids\": [\"15184390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BCR engagement induces progressive recruitment of CARMA1 into lipid rafts and association with PKCβ, which phosphorylates CARMA1 at S564, S649, and S657 in the serine-rich linker domain; mutation of S564 and S657 ablates CARMA1 function, whereas deletion of the linker causes constitutive, PKC-independent NF-κB activation.\",\n      \"method\": \"Lipid raft fractionation, in vitro kinase assay, site-directed mutagenesis, NF-κB reporter assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutagenesis plus functional reporter, replicated by parallel paper\",\n      \"pmids\": [\"16356855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PKCθ phosphorylates CARMA1 in vitro and in vivo at Ser552 (linker region) following TCR-CD28 costimulation; CARMA1 S552A mutant fails to mediate TCR-induced NF-κB activation in CARMA1-deficient T cells and fails to recruit downstream signaling components to the immunological synapse.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, site-directed mutagenesis, reconstitution of CARMA1-deficient T cells, immunological synapse imaging\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus mutagenesis plus cellular reconstitution with imaging\",\n      \"pmids\": [\"16356856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TAK1 is required for IKK activation in BCR signaling and interacts with phosphorylated CARMA1; this interaction is mediated by PKCβ. IKK is also recruited to the CARMA1-BCL10-MALT1 complex in a PKCβ-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, siRNA knockdown, PKCβ-deficient B cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with genetic (PKCβ-KO) and siRNA tools in multiple cell systems\",\n      \"pmids\": [\"16301747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IKKβ is required for initial CBM complex formation; upon engagement with the Carma1/BCL10/MALT1 complex, IKKβ phosphorylates BCL10 at its C-terminus, disrupting BCL10-MALT1 association and BCL10-mediated IKKγ ubiquitination — a negative regulatory feedback step.\",\n      \"method\": \"Genetic IKKβ-deficient T cells, in vitro kinase assay, mutagenesis of BCL10 phosphorylation sites, co-immunoprecipitation, cytokine measurement\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus genetic model plus mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"16818229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CaMKII is redistributed to the immune synapse upon T cell activation, phosphorylates CARMA1 on Ser109, and this phosphorylation facilitates the CARMA1-BCL10 interaction to enhance NF-κB activation.\",\n      \"method\": \"Computational expression analysis, CaMKII inhibitor/siRNA, in vitro kinase assay, Co-immunoprecipitation, NF-κB reporter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay plus Co-IP plus functional assay; single lab\",\n      \"pmids\": [\"16809782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA1 selectively regulates JNK2 (not JNK1) downstream of TCR signaling; BCL10 is inducibly associated with JNK2 and acts as a JIP-like scaffold assembling JNK2, MKK7, and TAK1; this CARMA1/BCL10-JNK2 axis controls c-Jun protein levels.\",\n      \"method\": \"Genetic KO mice for CARMA1/BCL10, Co-immunoprecipitation, JNK isoform-specific kinase assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with Co-IP and isoform-specific kinase assays, selective JNK2 regulation demonstrated\",\n      \"pmids\": [\"17189706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CARMA1 undergoes K48-linked polyubiquitination and proteasome-dependent degradation upon antigen receptor activation; ubiquitin acceptor sites reside in the SH3 and GUK domains; deletion of the Hook domain between SH3 and GUK induces constitutive ubiquitination; elimination of ubiquitination sites elevates NF-κB and JNK activation.\",\n      \"method\": \"Site-directed mutagenesis, proteasome inhibitor treatment, ubiquitin linkage-specific antibodies, NF-κB reporter, JNK assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus pharmacological inhibition plus linkage-specific antibodies\",\n      \"pmids\": [\"20008554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IKKβ contributes to formation of the CARMA1-BCL10-MALT1 complex in B cells by phosphorylating CARMA1 (in addition to PKCβ-mediated phosphorylation at Ser668); PKCβ-mediated Ser668 phosphorylation is essential for BCR-induced CBM association and subsequent IKK activation.\",\n      \"method\": \"Phospho-specific antibodies, PKCβ-deficient B cells, IKKβ inhibitor, Co-immunoprecipitation, kinase assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phospho-specific antibodies plus genetic PKCβ-KO plus inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"18086859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Caveolin-1 ligation of CD26 induces T cell NF-κB activation; the cytoplasmic tail of CD26 interacts with CARMA1, recruiting a complex of CD26/CARMA1/BCL10/IKK to lipid rafts.\",\n      \"method\": \"Co-immunoprecipitation, lipid raft fractionation, NF-κB reporter, soluble caveolin-1-Fc fusion protein stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional reporter, single lab\",\n      \"pmids\": [\"17287217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CARMA1 coiled-coil domain mediates constitutive oligomerization of CARMA1; disruption of coiled-coil structure impairs oligomerization and abrogates NF-κB activation; the CC1 subdomain is required for CARMA1 subcellular localization and CC2 for self-association.\",\n      \"method\": \"Co-immunoprecipitation of CARMA1 with itself, coiled-coil mutagenesis, subcellular localization imaging, NF-κB reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mutagenesis with localization and functional readouts; single lab\",\n      \"pmids\": [\"17428801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CARD11 contains a PKC-responsive inhibitory domain (ID) that controls the association of CARD11 with multiple signaling cofactors (BCL10, TRAF6, TAK1, IKKγ, caspase-8) through intramolecular interactions requiring both CARD and coiled-coil domains; TRAF6 and caspase-8 associate with CARD11 in a signal-inducible manner; CARD11 can recruit cofactors independently of BCL10 or MALT1.\",\n      \"method\": \"Domain mutagenesis, RNAi rescue assay, Co-immunoprecipitation in BCL10/MALT1-deficient cells, NF-κB reporter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — extensive domain mutagenesis, RNAi rescue, genetic-deficient cells, multiple cofactors tested\",\n      \"pmids\": [\"18625728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Oncogenic CARD11 coiled-coil domain mutations (e.g., L225LI) found in ABC-DLBCL induce constitutive NF-κB activation and enhance NF-κB activity upon antigen receptor stimulation when introduced into lymphoma cell lines.\",\n      \"method\": \"Sanger sequencing of DLBCL biopsies, transfection of mutant constructs into lymphoma cell lines, NF-κB reporter assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutation identification plus functional cell-based validation, landmark paper\",\n      \"pmids\": [\"18323416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cbl-b E3 ligase monoubiquitinates CARMA1, which disrupts CARMA1-BCL10 complex formation (without affecting CARMA1 protein stability), thereby suppressing NF-κB activation during NKT cell anergy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Cbl-b KO mice, CARMA1 KO NKT cells, IFN-γ production\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus in vivo ubiquitination assay plus Co-IP, mechanistic link established\",\n      \"pmids\": [\"19815501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PP2A (regulatory subunit Aα/PPP2R1A) interacts with CARMA1 and dephosphorylates PKCθ-dependent Ser645 phosphorylation on CARMA1; maintenance of this phosphorylation correlates with increased CBM complex formation, NF-κB activation, and IL-2/IFN-γ production.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro dephosphorylation assay, phospho-specific antibodies, cytokine assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro dephosphorylation plus genetic siRNA plus phospho-specific antibodies\",\n      \"pmids\": [\"21157432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HPK1 kinase interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the CARMA1 linker region at residues S549, S551, and S552 (distinct from PKC sites); CARMA1 S551A or S549A/S551A mutants fail to restore HPK1-mediated NF-κB activation in CARMA1-deficient T cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, reconstitution of CARMA1-deficient cells, NF-κB reporter\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus mutagenesis plus genetic reconstitution\",\n      \"pmids\": [\"19706536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CARMA1 serine 649 phosphorylation, occurring later and more persistently than S657 phosphorylation after antigen receptor stimulation, down-regulates CARMA1 activity; S649A mutation promotes enhanced IKK and JNK activation at low stimulation doses.\",\n      \"method\": \"Phospho-specific antibodies, site-directed mutagenesis, PKCβ-deficient B cells, DT40 CARMA1-deficient reconstitution, IKK/JNK assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phospho-specific antibodies plus mutagenesis plus genetic reconstitution, temporal kinetics resolved\",\n      \"pmids\": [\"19917688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Oncogenic CARD11 mutations F123I and L225LI induce hyperactivity by disrupting autoinhibition by the CARD11 inhibitory domain (ID): they disrupt ID-mediated intramolecular interactions, bypass the requirement for ID phosphorylation during TCR signaling, and selectively enhance CARD11 affinity for BCL10.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, dominant-negative ID peptide, phosphorylation-mimetic/defective mutants, NF-κB reporter\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mutagenesis plus intramolecular interaction assays with multiple oncogenic mutations tested\",\n      \"pmids\": [\"20799731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Calcineurin (activated by calcium) positively regulates CBM complex formation by dephosphorylating BCL10, promoting CARMA1-BCL10-MALT1 assembly; calcineurin A is physically associated with the CBM complex.\",\n      \"method\": \"Cyclosporin A/FK506 pharmacological inhibition, EGTA-AM calcium chelation, calcineurin siRNA knockdown, in vitro dephosphorylation, Co-immunoprecipitation, NF-κB reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro dephosphorylation plus multiple pharmacological/genetic tools plus Co-IP\",\n      \"pmids\": [\"21199863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"OX40 (a TNFR family member) assembles a signalosome containing TRAF2, RIP, IKKα/β/γ as well as CARMA1, MALT1, BCL10, and PKC in membrane microdomains independently of TCR engagement; NF-κB activation by OX40 requires CARMA1 and PKC.\",\n      \"method\": \"Co-immunoprecipitation, membrane microdomain fractionation, genetic-deficient cells, NF-κB reporter, T cell survival assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus fractionation plus functional analysis; single lab\",\n      \"pmids\": [\"21282629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAP associates with CARMA1 and is required for TCR-stimulated assembly of the CARMA1-BCL10-MALT1 complex; a distinct region of ADAP mediates CARMA1 association and NF-κB activation, separable from ADAP's role in adhesion regulation.\",\n      \"method\": \"ADAP-deficient T cells, Co-immunoprecipitation, NF-κB nuclear translocation assay, IκBα phosphorylation/degradation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic ADAP-deficient cells plus Co-IP plus domain separation study\",\n      \"pmids\": [\"17478723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The reconstituted CBM signalosome forms a helical filamentous assembly in which substoichiometric CARMA1 nucleates BCL10 CARD filaments in a highly cooperative process; crystallography, NMR, and EM reveal the Bcl10 CARD filament structure and CARMA1-BCL10 interface; structure-guided mutagenesis confirmed these interfaces for MALT1 activation in vitro and NF-κB activation in cells.\",\n      \"method\": \"In vitro reconstitution, cryo-EM, X-ray crystallography, NMR, electron microscopy, site-directed mutagenesis, NF-κB reporter\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution plus structure (crystallography, NMR, EM) plus mutagenesis validation in vitro and in cells\",\n      \"pmids\": [\"24074955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP9X deubiquitinating enzyme interacts with BCL10 in the CBM complex and removes TCR-induced ubiquitin chains from BCL10, which facilitates CARMA1-BCL10-MALT1 association and is required for NF-κB activation in T cells.\",\n      \"method\": \"Co-immunoprecipitation, USP9X siRNA knockdown, ubiquitination assay, NF-κB reporter, T cell proliferation/cytokine assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus siRNA knockdown plus ubiquitination assay; single lab\",\n      \"pmids\": [\"23690623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STUB1 (an E3 ubiquitin ligase) constitutively interacts with CARMA1 and catalyzes Lys-27-linked ubiquitination of CARMA1 upon TCR stimulation; STUB1 knockdown diminishes TCR-induced NF-κB activation and IL-2 production.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay with linkage-specific mutant ubiquitin, NF-κB reporter, cytokine assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus K27-specific ubiquitination assay plus siRNA functional readout; single lab\",\n      \"pmids\": [\"23322406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CARMA1 (and MALT1 but not BCL10) is required for optimal TCR/CD28-induced mTORC1 activation in T cells; MALT1 catalytic activity is required for CD4+ T cell proliferation and increased metabolic flux in activated T cells.\",\n      \"method\": \"Genetic-deficient cells, MALT1 catalytic inhibitor, mTOR substrate phosphorylation assay, metabolic flux assay, T cell proliferation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic CBM component-deficient cells plus pharmacological MALT1 inhibition plus multiple metabolic readouts\",\n      \"pmids\": [\"24917592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA1 clustering through SH3-GUK domain interactions (intra- and intermolecular) is required for activation-induced microcluster formation at the immunological synapse and for TCR-induced and oncogenic NF-κB signaling; disruption of SH3-GUK interactions abolishes CARMA1 microclusters and NF-κB activation.\",\n      \"method\": \"SH3/GUK mutagenesis, live-cell confocal imaging of synapse microclusters, Co-immunoprecipitation, NF-κB reporter, ABC-DLBCL cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis plus live-cell imaging plus functional reporter, mechanistic link established\",\n      \"pmids\": [\"25602919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNF181, an E3 ubiquitin ligase identified by BRIC screening, interacts with CARD11 and ubiquitinates BCL10 to negatively regulate antigen receptor signaling to NF-κB; RNF181 limits DLBCL cell proliferation dependent on aberrant CARD11 signaling.\",\n      \"method\": \"BRIC interaction screen, Co-immunoprecipitation, in vitro ubiquitination assay, BCL10 protein level assay, NF-κB reporter, DLBCL cell proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vitro ubiquitination assay plus Co-IP plus functional cell proliferation; single lab\",\n      \"pmids\": [\"26711259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCL10 undergoes TCR-induced linear (LUBAC/HOIP-mediated) polyubiquitination, which is required for association with NEMO/IKKγ; CARD11 promotes this by co-recruiting BCL10 and HOIP via its coiled-coil domain; oncogenic CARD11 variants spontaneously induce Lin(Ub)n-BCL10 correlating with enhanced HOIP and BCL10 binding.\",\n      \"method\": \"Linear ubiquitin-specific antibodies, site-directed mutagenesis of BCL10 lysines, HOIP/CARD11 domain mutagenesis, Co-immunoprecipitation, NF-κB reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — linkage-specific ubiquitin detection plus mutagenesis plus Co-IP, mechanistic framework clearly established\",\n      \"pmids\": [\"27777308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The CARD11 inhibitory domain (ID) contains four repressive elements (REs) that function cooperatively and redundantly to prevent spontaneous NF-κB activation; each RE contributes to closed inactive state maintenance and prevention of BCL10 binding; oncogenic mutations disrupt intramolecular interactions mediated by multiple REs.\",\n      \"method\": \"Domain mutagenesis, intramolecular interaction assay, quantitative NF-κB reporter assay, domain-deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic mutagenesis of four REs with quantitative signaling output plus intramolecular interaction assay\",\n      \"pmids\": [\"26884334\", \"26884335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Germline hypomorphic CARD11 mutations cause loss-of-function and dominant-interfering activity for antigen receptor-induced NF-κB and mTORC1 signaling; glutamine supplementation partially rescues mTORC1 and IFN-γ production defects, indicating CARD11 is required for glutamine import into T cells.\",\n      \"method\": \"Transfection of mutant constructs, NF-κB and mTORC1 reporter assays, patient primary T cell functional assays, glutamine supplementation rescue experiment\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in both cell lines and patient primary cells, metabolic rescue experiment\",\n      \"pmids\": [\"28628108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of BCL10 CARD filament at 4.0 Å redefines CARD-CARD interactions; BCL10 polymerizes in a unidirectional manner in time-lapse confocal imaging; CARMA1 serves as a hub nucleating star-shaped BCL10 filament networks and decreases the lag period of BCL10 polymerization; MALT1 immediately dimerizes on BCL10 filaments and TRAF6 cooperatively decorates CBM filaments in higher-order assemblies.\",\n      \"method\": \"Cryo-EM structure determination, time-lapse confocal imaging, in vitro polymerization assay, EM of MALT1/TRAF6 decoration\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus live-cell imaging plus in vitro reconstitution, single rigorous study\",\n      \"pmids\": [\"29382759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structure of a CARD9 region containing an extensive CARD-coiled-coil interface reveals the structural basis for autoinhibition; disruption of this interface leads to hyperactivation and Bcl10-templating filament formation in vitro for both CARD9 and CARD11; structure of the CARD9 filament illuminates mechanisms of CARD11 oncogenic mutations and how autoinhibition is relieved during canonical activation.\",\n      \"method\": \"X-ray crystallography of autoinhibited CARD9, cryo-EM of CARD9 filament, cell-based hyperactivation assays, in vitro filament polymerization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus cryo-EM plus in vitro reconstitution plus cell-based mutagenesis\",\n      \"pmids\": [\"31296852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GAKIN (a kinesin-3 family member) associates with CARD11 in a signal-dependent manner, competes with BCL10 for CARD11 association, and dynamically localizes to the immunological synapse to redistribute CARD11 from the central to a distal region, thereby negatively regulating TCR signaling to NF-κB.\",\n      \"method\": \"Expression-cloning screen, Co-immunoprecipitation, live-cell imaging at immunological synapse, NF-κB reporter, competition binding assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — expression cloning plus Co-IP plus live-cell imaging plus functional NF-κB assay\",\n      \"pmids\": [\"21145487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A quantitative signaling screen identifies gain-of-function CARD11 mutations in the CARD and LATCH domains; LATCH domain functions with the CARD to promote autoinhibition; mutations in LATCH or CARD disrupt inhibitory domain binding, promote BCL10 association, induce BCL10 ubiquitination, NF-κB activation, and human lymphoma cell survival.\",\n      \"method\": \"High-throughput quantitative NF-κB signaling screen, domain mutagenesis, Co-immunoprecipitation, ubiquitination assay, lymphoma cell survival assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — unbiased quantitative screen plus mutagenesis plus Co-IP plus functional cell survival assay\",\n      \"pmids\": [\"23149938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Complete human CARD11 deficiency (biallelic p.Arg837* loss-of-function) prevents CBM complex formation, severely impairs NF-κB, JNK, and MALT1 paracaspase activation in B and T cells, and causes a developmental block in B cells at the naive/type 1 transitional stage with impaired T follicular helper cell development.\",\n      \"method\": \"Whole-exome sequencing, immunoblot signaling assays, flow cytometry immunophenotyping, MALT1 paracaspase activity assay, transcriptomics, hematopoietic stem cell transplantation functional restoration\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical and cellular assays in patient cells with functional restoration by HSCT\",\n      \"pmids\": [\"33872653\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARD11 (CARMA1) is a lymphocyte-specific CARD-MAGUK scaffold protein that is held in a closed, autoinhibited state by an inhibitory domain (containing four repressive elements and requiring CARD-coiled-coil intramolecular contacts); upon antigen receptor stimulation, PKCβ/θ (and additional kinases HPK1, CaMKII) phosphorylate CARD11's linker/inhibitory domain, relieving autoinhibition and allowing CARD11 to oligomerize, recruit to lipid rafts and the immunological synapse, and nucleate BCL10 CARD filaments through CARD-CARD interactions, which in turn recruit MALT1 (forming the CBM signalosome) that activates TRAF6/TAK1/IKK for canonical NF-κB and JNK2/AP-1 signaling, as well as mTORC1 activation and LUBAC-mediated linear ubiquitination of BCL10-NEMO; negative regulation is achieved by PP2A dephosphorylation of CARD11, K48-polyubiquitination and proteasomal degradation via its SH3-GUK MAGUK domain, Cbl-b monoubiquitination, and GAKIN-mediated displacement from the synapse, while oncogenic gain-of-function mutations in the coiled-coil, CARD, or LATCH domains disrupt autoinhibition to drive constitutive NF-κB activation in lymphomas, and germline loss-of-function mutations cause combined immunodeficiency.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CARD11 (CARMA1) is a lymphocyte-specific scaffold protein that couples antigen receptor and costimulatory signals to NF-κB, JNK2/AP-1, and mTORC1 activation. In its resting state, an intramolecular inhibitory domain (ID) containing four cooperatively acting repressive elements maintains CARD11 in a closed conformation through CARD–coiled-coil contacts; upon TCR or BCR engagement, PKCθ/PKCβ (and additional kinases HPK1 and CaMKII) phosphorylate the linker/ID region, relieving autoinhibition and enabling CARD11 oligomerization via coiled-coil and SH3-GUK domain interactions, recruitment to lipid raft microclusters at the immunological synapse, and nucleation of cooperative BCL10 CARD filaments that recruit MALT1 and TRAF6 into higher-order CBM signalosomes that activate the TAK1–IKK cascade and LUBAC-mediated linear ubiquitination of BCL10–NEMO [PMID:24074955, PMID:29382759, PMID:18625728, PMID:27777308, PMID:25602919]. Negative regulation is achieved by PP2A-mediated dephosphorylation, Cbl-b monoubiquitination disrupting BCL10 binding, K48-linked polyubiquitination and proteasomal degradation via the SH3-GUK domain, and GAKIN-mediated displacement from the synapse [PMID:21157432, PMID:19815501, PMID:20008554, PMID:21145487]. Gain-of-function mutations in the coiled-coil, CARD, or LATCH domains that disrupt autoinhibition drive constitutive NF-κB activation in diffuse large B-cell lymphoma, while biallelic loss-of-function mutations cause combined immunodeficiency with impaired B and T cell development [PMID:18323416, PMID:23149938, PMID:33872653].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of CARD11 as a CARD-MAGUK scaffold that binds BCL10 via CARD-CARD interactions and activates NF-κB established the founding molecular connection between a MAGUK-family protein and the NF-κB pathway in lymphocytes.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, NF-κB reporter assays, and confocal microscopy in transfected cells\",\n      \"pmids\": [\"11278692\", \"11356195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli activating CARD11 were not yet identified\", \"Mechanism of BCL10 phosphorylation downstream of CARD11 unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that CARD11 selectively mediates antigen receptor (TCR/BCR)–induced but not TNFα-induced NF-κB and JNK signaling, acting upstream of IKK in lipid rafts, defined its pathway specificity and placed it at the apex of adaptive immune NF-κB signaling.\",\n      \"evidence\": \"RNAi knockdown, reconstitution with domain mutants, lipid raft fractionation, somatic mutagenesis screen, and dominant-negative approaches in T cells\",\n      \"pmids\": [\"12356734\", \"12154360\", \"12154356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The activating kinase upstream of CARD11 was not identified\", \"How CARD11 associates with lipid rafts was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic knockout of CARD11 in mice confirmed it is essential for T and B cell immunity, NF-κB/JNK activation downstream of antigen receptors, and identified the coiled-coil domain as a critical structural determinant for pathway-specific signaling.\",\n      \"evidence\": \"CARD11 knockout mice, ENU forward genetic screen, CARD-deleted knock-in mice, proliferation and cytokine assays\",\n      \"pmids\": [\"12818158\", \"12818157\", \"12867038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular mechanism by which the coiled-coil domain contributes to signaling was unknown\", \"Whether CARD11 signals independently of BCL10 was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"CARD11 was shown to orchestrate a trimolecular CBM signalosome by recruiting BCL10, MALT1, PKCθ, and IKK into lipid raft aggregates at the immunological synapse, with MALT1 associating with CARD11 independently of BCL10.\",\n      \"evidence\": \"Reconstitution of CARD11-deficient T cells, lipid raft fractionation, live-cell synapse imaging, Co-immunoprecipitation in BCL10-deficient backgrounds\",\n      \"pmids\": [\"14673152\", \"15520247\", \"14754896\", \"15184390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The activating phosphorylation events on CARD11 were not yet mapped\", \"Stoichiometry of the CBM complex was unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"PKCβ and PKCθ were identified as the direct activating kinases that phosphorylate CARD11's linker region (S552/S564/S649/S657/S668), and deletion of the linker was found to cause constitutive NF-κB activation, revealing a phosphorylation-regulated autoinhibitory switch.\",\n      \"evidence\": \"In vitro kinase assays, phospho-specific antibodies, site-directed mutagenesis, reconstitution of CARD11-deficient T and B cells, synapse imaging\",\n      \"pmids\": [\"16356855\", \"16356856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Additional kinases contributing to CARD11 activation were not yet known\", \"Structural basis of autoinhibition was unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"CaMKII was identified as an additional CARD11 kinase (Ser109), and CARD11 was shown to selectively regulate JNK2 via a BCL10-scaffolded MKK7/TAK1 module, broadening the effector outputs of the CBM complex beyond NF-κB.\",\n      \"evidence\": \"CaMKII inhibitor/siRNA, in vitro kinase assay, JNK isoform-specific kinase assays in CARMA1/BCL10 KO mice\",\n      \"pmids\": [\"16809782\", \"17189706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological importance of CaMKII phosphorylation relative to PKC was unclear\", \"How JNK2 selectivity is achieved structurally was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"ADAP was shown to associate with CARMA1 and promote CBM assembly, while CARD11's coiled-coil domain was demonstrated to mediate constitutive self-oligomerization required for NF-κB activation, revealing both an upstream adaptor input and the oligomerization mechanism.\",\n      \"evidence\": \"ADAP-deficient T cells, Co-immunoprecipitation, coiled-coil mutagenesis, subcellular localization imaging\",\n      \"pmids\": [\"17478723\", \"17428801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ADAP-CARD11 interaction is regulated was unknown\", \"Whether oligomerization suffices for activation or requires additional signals was unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of the inhibitory domain (ID) as a PKC-responsive switch that controls CARD11 association with multiple cofactors (BCL10, TRAF6, TAK1, NEMO, caspase-8) through intramolecular CARD-coiled-coil contacts established the autoinhibition model, while oncogenic coiled-coil mutations in ABC-DLBCL were shown to constitutively activate NF-κB by disrupting this mechanism.\",\n      \"evidence\": \"Extensive domain mutagenesis in BCL10/MALT1-deficient cells, RNAi rescue, sequencing of DLBCL biopsies with functional validation in lymphoma lines\",\n      \"pmids\": [\"18625728\", \"18323416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Number and identity of repressive elements within the ID were not mapped\", \"Structural basis of oncogenic mutation hyperactivity was unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Multiple negative regulatory mechanisms were identified: PP2A dephosphorylates PKCθ-dependent CARD11 Ser645 to terminate signaling, Cbl-b monoubiquitinates CARD11 to disrupt BCL10 binding during NKT anergy, and HPK1 phosphorylates distinct linker residues to modulate activation, revealing that CARD11 integrates opposing phosphorylation/ubiquitination signals.\",\n      \"evidence\": \"In vitro dephosphorylation, phospho-specific antibodies, siRNA, Cbl-b/CARMA1 KO mice, HPK1 in vitro kinase assay with mutagenesis, reconstitution\",\n      \"pmids\": [\"21157432\", \"19815501\", \"19706536\", \"19917688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of these opposing modifications was not fully resolved\", \"Whether PP2A and Cbl-b act on the same or distinct pools of CARD11 was unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"GAKIN kinesin was identified as a signal-dependent negative regulator that competes with BCL10 for CARD11 binding and physically displaces CARD11 from the central synapse, while oncogenic mutations were shown to bypass ID autoinhibition by disrupting intramolecular interactions.\",\n      \"evidence\": \"Expression-cloning screen, live-cell synapse imaging, competition binding assay, Co-immunoprecipitation, phosphorylation-mimetic mutants\",\n      \"pmids\": [\"21145487\", \"20799731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Motor activity requirement for GAKIN's negative regulation was not tested\", \"How oncogenic mutations alter CARD11 conformational dynamics structurally was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A quantitative signaling screen identified gain-of-function mutations in the CARD and LATCH domains, establishing that the LATCH cooperates with the CARD to maintain autoinhibition, and that disruption of either promotes BCL10 association, ubiquitination, and lymphoma cell survival.\",\n      \"evidence\": \"High-throughput NF-κB signaling screen, domain mutagenesis, Co-immunoprecipitation, lymphoma cell survival assay\",\n      \"pmids\": [\"23149938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural definition of the LATCH domain was lacking\", \"Precise intramolecular contacts between LATCH and ID were not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural reconstitution revealed that CARD11 nucleates cooperative BCL10 CARD filament polymerization in a helical assembly, providing the first structural framework for how substoichiometric CARD11 amplifies downstream signaling through a prion-like templating mechanism.\",\n      \"evidence\": \"Cryo-EM, X-ray crystallography, NMR of BCL10 CARD filament, in vitro reconstitution, structure-guided mutagenesis validated in cells\",\n      \"pmids\": [\"24074955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length CARD11 structure was not determined\", \"Stoichiometry of CARD11 within native signalosomes in cells was unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CARD11 was shown to be required for TCR/CD28-induced mTORC1 activation, linking the CBM signalosome to metabolic reprogramming beyond NF-κB.\",\n      \"evidence\": \"Genetic CARD11-deficient cells, mTOR substrate phosphorylation assay, MALT1 catalytic inhibitor, metabolic flux measurement\",\n      \"pmids\": [\"24917592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting CBM to mTORC1 was not identified\", \"Whether CARD11 regulates amino acid transport directly was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The ID was dissected into four cooperatively acting repressive elements, and CARD11 was shown to promote LUBAC/HOIP-mediated linear ubiquitination of BCL10 for NEMO recruitment via its coiled-coil domain, completing the picture of how CARD11 coordinates both activation and ubiquitin-dependent signaling outputs.\",\n      \"evidence\": \"Systematic RE mutagenesis with quantitative NF-κB readout, linear ubiquitin-specific antibodies, HOIP/CARD11 coiled-coil domain mutagenesis, Co-IP\",\n      \"pmids\": [\"26884334\", \"26884335\", \"27777308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether each RE has distinct regulatory inputs was not resolved\", \"How LUBAC is recruited to CARD11 structurally was unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"High-resolution cryo-EM of the BCL10 CARD filament and time-lapse imaging showed CARD11 acts as a hub nucleating star-shaped BCL10 filament networks, with MALT1 dimerizing immediately on filaments and TRAF6 cooperatively decorating them, providing an integrated structural model of the CBM signalosome.\",\n      \"evidence\": \"4.0 Å cryo-EM structure, time-lapse confocal imaging, in vitro polymerization, EM of MALT1/TRAF6 decoration\",\n      \"pmids\": [\"29382759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length activated CARD11 structure was still missing\", \"In vivo filament dynamics and turnover were not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Crystal structure of the CARD9 CARD–coiled-coil interface and cryo-EM of its filament provided a structural template for understanding CARD11 autoinhibition: disruption of the analogous CARD–coiled-coil interface in CARD11 leads to hyperactivation and spontaneous BCL10 filament templating.\",\n      \"evidence\": \"X-ray crystallography of autoinhibited CARD9, cryo-EM of CARD9 filament, cell-based CARD11 hyperactivation assays, in vitro filament polymerization\",\n      \"pmids\": [\"31296852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CARD11 CARD-coiled-coil structure was not determined\", \"Conformational transition from autoinhibited to active CARD11 was not visualized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Complete human CARD11 deficiency was shown to cause combined immunodeficiency with impaired B cell development, absent NF-κB/JNK/MALT1 paracaspase activation, and defective T follicular helper cell generation, confirming CARD11 as an essential non-redundant node in human adaptive immunity.\",\n      \"evidence\": \"Whole-exome sequencing identifying biallelic p.Arg837* in patients, immunophenotyping, signaling assays in patient cells, functional restoration by HSCT\",\n      \"pmids\": [\"33872653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether partial loss-of-function alleles produce a milder immunodeficiency spectrum was not fully characterized\", \"Contribution of CARD11 to innate lymphoid cell function in humans was not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of full-length CARD11 in both autoinhibited and activated conformations, the precise mechanism linking CBM assembly to mTORC1 activation, and the in vivo dynamics of CARD11 filament formation and disassembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length CARD11 structure in either state\", \"Mechanism connecting CBM to mTORC1/metabolic reprogramming is molecularly undefined\", \"In vivo filament dynamics and stoichiometry at the synapse have not been measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 8, 22, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 39, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8, 9, 12, 36]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 7, 13, 45]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 17, 35, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 44]}\n    ],\n    \"complexes\": [\n      \"CBM signalosome (CARD11-BCL10-MALT1)\",\n      \"CARD11-IKK complex\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"MALT1\",\n      \"TRAF6\",\n      \"NEMO\",\n      \"PRKCB\",\n      \"PRKCQ\",\n      \"PPP2R1A\",\n      \"KIF13B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}