{"gene":"MALT1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2008,"finding":"TCR stimulation induces recruitment of A20 into a MALT1-BCL10 complex, leading to MALT1-mediated proteolytic cleavage of A20 after arginine 439, impairing A20's NF-κB-inhibitory function. API2-MALT1 fusion likewise cleaves A20.","method":"Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis (R439 cleavage site identification), cell-based NF-κB reporter assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage assay with mutagenesis, replicated in multiple cell systems","pmids":["18223652"],"is_preprint":false},{"year":2009,"finding":"A20 functions as a deubiquitinating enzyme for MALT1, removing K63-linked ubiquitin chains from MALT1 to prevent sustained IKK complex recruitment and limit NF-κB signaling duration after TCR/CD28 stimulation. Reciprocally, MALT1 paracaspase activity cleaves and inactivates A20.","method":"Malt1-/- T cell reconstitution, antagonistic peptides, ubiquitin chain analysis, IKK activity assays, IL-2 production measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic reconstitution plus biochemical ubiquitin assays with multiple orthogonal methods","pmids":["19494296"],"is_preprint":false},{"year":2007,"finding":"TRAF6 associates with MALT1 upon T cell activation and mediates K63-linked polyubiquitination of MALT1 at multiple C-terminal lysine residues. These ubiquitin chains serve as a docking surface for NEMO/IKKγ recruitment, linking CBM complex formation to IKK/NF-κB activation.","method":"Co-immunoprecipitation, in vitro ubiquitination assay with TRAF6 as E3, Malt1-/- T cell reconstitution with ubiquitin-acceptor lysine mutants, IL-2 production readout","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of ubiquitination plus genetic rescue in knockout cells","pmids":["17948050"],"is_preprint":false},{"year":2011,"finding":"MALT1 proteolytically inactivates CYLD, which is required for TCR-induced JNK activation and expression of a subset of JNK-dependent genes. This cleavage is also induced by the oncogenic API2-MALT1 fusion.","method":"In vitro cleavage assay, Malt1-/- cell reconstitution, JNK activation assays, gene expression profiling, paracaspase inhibitor treatment","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro cleavage demonstrated, genetic and pharmacological validation with defined phenotypic readout","pmids":["21448133"],"is_preprint":false},{"year":2011,"finding":"MALT1 cleaves the NF-κB family member RelB after Arg-85, inducing its proteasomal degradation and specifically enabling DNA binding of RelA- and c-Rel-containing NF-κB complexes to drive canonical NF-κB target gene expression.","method":"In vitro cleavage assay, site-directed mutagenesis (R85 site), proteasome inhibitor studies, NF-κB DNA-binding assays, DLBCL cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage assay with mutagenesis plus functional cellular validation","pmids":["21873235"],"is_preprint":false},{"year":2012,"finding":"MALT1 protease activity is dependent on dimerization; the unliganded protease exists as a dimer in an inactive state and undergoes substantial conformational changes upon substrate binding. The C-terminal Ig-like domain is required for MALT1 activity. Dimer interface mutations abrogate protease activity in cells.","method":"Crystal structure determination, biochemical dimerization assays, mutagenesis of dimer interface, cell-based protease activity assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus functional validation in cells","pmids":["22366302"],"is_preprint":false},{"year":2012,"finding":"MALT1 paracaspase cleaves specifically after arginine residues with stringent peptide length constraints. Dimerization activates both full-length MALT1 and its catalytic domain without cleavage, analogous to apical caspases. CYLD is cleaved by MALT1 with kcat/Km values comparable to optimal peptidyl substrates.","method":"Positional-scanning peptidyl substrate libraries, recombinant protein expression and purification, in vitro kinetic assays, dimerization studies","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with substrate library profiling and kinetic measurements","pmids":["22309193"],"is_preprint":false},{"year":2014,"finding":"MALT1 undergoes auto-proteolytic cleavage after Arg-149 (between the death domain and first Ig-like region) upon antigen receptor stimulation. This autocleavage does not affect protease activity but is required for optimal NF-κB-dependent transcription of target genes (IL-2, CSF2) downstream of nuclear NF-κB accumulation.","method":"Site-directed mutagenesis (R149A), Jurkat T cell reconstitution, NF-κB reporter assays, transcriptome analysis, IκBα phosphorylation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with transcriptome validation and multiple functional readouts","pmids":["25105596"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of BCL10 CARD filament at 4.0-Å resolution shows CARMA1 nucleates unidirectional BCL10 polymerization. MALT1 cooperatively interacts with BCL10 filaments and immediately dimerizes on the filamentous scaffold. TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies for all-or-none downstream pathway activation.","method":"Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, pulldown assays, negative-stain EM","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with live imaging and biochemical validation","pmids":["29382759"],"is_preprint":false},{"year":2006,"finding":"CARMA3-BCL10-MALT1 mediates angiotensin II receptor (GPCR)-induced NF-κB activation in non-immune hepatocytes, acting through IKKγ ubiquitination. Dominant-negative mutants, RNAi, or gene targeting of any CBM component abolishes Ang II-dependent NF-κB activation.","method":"Dominant-negative mutants, RNAi knockdown, Bcl10-/- mouse embryonic fibroblasts, NF-κB reporter assays, cytokine production measurement in vivo","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple loss-of-function approaches with in vitro and in vivo validation","pmids":["17101977"],"is_preprint":false},{"year":2006,"finding":"BCL10 and MALT1 are essential mediators of lysophosphatidic acid (LPA)-induced NF-κB activation downstream of G protein-coupled receptors in non-immune fibroblasts, cooperating with PKCs selectively for NF-κB but dispensable for JNK, p38, ERK, and Akt pathways.","method":"Bcl10-/- and Malt1-/- mouse embryonic fibroblasts, IκBα degradation assays, NF-κB activation assays, kinase pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with pathway-selective functional analysis","pmids":["17095601"],"is_preprint":false},{"year":2007,"finding":"MALT1 selectively activates c-Rel but not RelA in B cells after BCR stimulation. MALT1 participates in survival signaling but is not required for IKK recruitment into lipid rafts, IKK activation, or RelA induction, demonstrating selective control of a c-Rel-dependent transcriptional subprogram.","method":"Malt1-/- B cells, lipid raft fractionation, NF-κB subunit-specific assays, cell survival and proliferation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with subunit-resolved mechanistic analysis","pmids":["17660823"],"is_preprint":false},{"year":2016,"finding":"MALT1 alternative splicing generates two conserved isoforms: MALT1A (exon7-included) and MALT1B. MALT1A facilitates TRAF6 recruitment, augmenting MALT1 scaffolding function but not protease activity. hnRNP U suppresses exon7 inclusion; TCR stimulation induces MALT1A expression. Selective MALT1A depletion impairs T cell signaling and activation.","method":"Isoform-selective knockdown, Co-immunoprecipitation of TRAF6, NF-κB signaling assays, hnRNP U knockdown, T cell activation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — isoform-selective manipulation with multiple orthogonal mechanistic readouts","pmids":["27068814"],"is_preprint":false},{"year":2019,"finding":"MALT1 proteolytically cleaves N4BP1 (an HIV-1 restriction factor with RNase activity) at Arg-509 upon T cell activation, inactivating N4BP1's ability to degrade viral mRNA and thereby facilitating reactivation of latent HIV-1 proviruses.","method":"RNA-binding protein screen, N4BP1 cleavage assay, MALT1 knockout/knockdown studies, HIV-1 reactivation assay, mutational analysis of cleavage site","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1-2 — cleavage site identified by mutagenesis, knockout validation, and functional viral reactivation readout","pmids":["31133753"],"is_preprint":false},{"year":2016,"finding":"CARD14 physically interacts with MALT1 and activates MALT1 proteolytic activity in keratinocytes. Psoriasis-associated CARD14 mutations enhance this interaction constitutively, driving BCL10- and MALT1-dependent NF-κB, p38, and JNK activation, and inflammatory gene expression.","method":"Co-immunoprecipitation, MALT1 protease activity assays, MALT1 siRNA/inhibitor studies, primary human keratinocyte assays with psoriasis-mutant CARD14","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction demonstrated, protease activity measured, pharmacological and genetic validation","pmids":["27113748"],"is_preprint":false},{"year":2016,"finding":"MALT1 cleaves the LUBAC subunit HOIL1 upon antigen receptor engagement. HOIL1 is constitutively processed in ABC-DLBCL cells with aberrant MALT1 activity. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, identifying HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1.","method":"In vitro cleavage assay, MALT1 inhibitor treatment, overexpression of cleavage-resistant HOIL1 mutant, NF-κB reporter assay, cytokine measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro cleavage plus cleavage-resistant mutant functional rescue","pmids":["27006117"],"is_preprint":false},{"year":2005,"finding":"MALT1 contains nuclear export signal (NES) sequences in its C-terminal region, causing constitutive nucleocytoplasmic shuttling. MALT1 regulates cytoplasmic localization of BCL10 through this NES-dependent export mechanism.","method":"Deletion mutant analysis, leptomycin B treatment (NES inhibitor), cellular fractionation and localization studies","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with pharmacological validation, but single lab","pmids":["16123224"],"is_preprint":false},{"year":2009,"finding":"MALT1 is required for BAFF-induced non-canonical NF-κB signaling (phosphorylation of NF-κB2/p100, p100 degradation, RelB nuclear translocation) in marginal zone B cells. MALT1 interacts with TRAF3, a negative regulator of BAFF receptor signaling, and MALT1 deficiency results in elevated TRAF3 levels.","method":"Malt1-/- B cells, Co-immunoprecipitation (MALT1-TRAF3), NF-κB2 processing assays, B cell survival assays, in vivo BAFF-overexpression model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with mechanistic Co-IP and multiple functional readouts in vitro and in vivo","pmids":["19917778"],"is_preprint":false},{"year":2008,"finding":"BCL10-MALT1 interaction involves multiple protein domains: the Ig-like domains of MALT1 interact with a post-CARD region of BCL10, but the MALT1 death domain and BCL10 CARD also contribute. FRET analysis identified the MALT1 death domain contribution in live T cells. BCL10 CARD residues Asp80 and Glu84 in helix 5 directly contact MALT1.","method":"Co-immunoprecipitation, FRET analysis in T cells, BCL10 point mutant analysis, molecular modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus FRET plus mutagenesis, single lab","pmids":["18806265"],"is_preprint":false},{"year":2019,"finding":"TRAF6 plays a dual role: it recruits to MALT1 for NF-κB signaling in activated T cells, but also counteracts basal MALT1 protease activity in resting T cells. Loss of TRAF6-mediated homeostatic suppression leads to severe autoimmune inflammation fully rescued by MALT1 protease inactivation.","method":"Genetically engineered mouse models (T cell-specific TRAF6 knockout), biochemical MALT1 protease activity assays, pharmacological MALT1 inhibitor rescue, autoimmune phenotype analysis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic models with biochemical validation and therapeutic rescue","pmids":["34767456"],"is_preprint":false},{"year":2019,"finding":"MALT1 protease is constitutively active in psoriatic CD4+ and γδ T cells and stabilizes c-Jun by proteolytic cleavage, thereby supporting GLS1 (glutaminase 1) expression. This promotes glutaminolysis, H3 acetylation at the Il17a promoter, and Th17/γδT17 cell differentiation contributing to psoriasis.","method":"MALT1 inhibitor treatment, c-Jun cleavage assay, chromatin immunoprecipitation (H3 acetylation), GLS1 expression analysis, mouse psoriasis models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological inhibition plus chromatin analysis, single lab","pmids":["32831293"],"is_preprint":false},{"year":2019,"finding":"BCL10-controlled MALT1 paracaspase activity is essential for the immune-suppressive function of regulatory T cells (Tregs) but not for their differentiation per se. In tumor models, acute genetic BCL10 blockade in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses.","method":"T cell-conditional BCL10 knockout mice, MALT1 protease-dead knock-in mice, melanoma mouse models, Treg suppression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional genetic models with defined functional readout, replicated pharmacologically","pmids":["31138793"],"is_preprint":false},{"year":2015,"finding":"MALT1 protease-dead knock-in mice reveal that MALT1 protease activity is required for marginal zone and B1 B cell development, T cell proliferation and IL-2 production, dendritic cell cytokine responses to Dectin-1/2/Mincle, and immune homeostasis. Protease-dead mice develop mixed inflammatory cell infiltrates in multiple organs.","method":"MALT1 protease-dead knock-in mouse generation, flow cytometry of lymphocyte subsets, proliferation assays, in vivo immunization, dendritic cell cytokine assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse with comprehensive immune phenotyping across multiple cell types","pmids":["25665967"],"is_preprint":false},{"year":2014,"finding":"TCR signals to NF-κB are transmitted through a cytosolic p62-BCL10-MALT1-IKK signalosome. p62 is required for clustering of BCL10-MALT1 with IKK in effector T cells. TAK1 and IKK inhibition block IKK phosphorylation but not signalosome assembly, indicating IKK activation occurs after signalosome formation.","method":"Confocal imaging of signalosome assembly, p62-/- T cells, kinase inhibitor studies, co-immunoprecipitation","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic knockout with imaging and biochemical validation, single lab","pmids":["24825920"],"is_preprint":false},{"year":2019,"finding":"The E3 ubiquitin ligase HECTD3 promotes K27-linked and K29-linked non-degradative polyubiquitination of MALT1 at K648, which is required for NF-κB activation and Th17 cell differentiation in experimental autoimmune encephalomyelitis.","method":"Hectd3-/- mice, ubiquitination assays with linkage-specific antibodies, Malt1 K648 mutagenesis, NF-κB activation assays, Th17 differentiation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with site-specific mutagenesis and functional validation","pmids":["30741923"],"is_preprint":false},{"year":2019,"finding":"MALT1 phosphorylation at multiple C-terminal serine residues occurs after TCR/CD28 co-stimulation, mediated by CK1α. CK1α is essential for both CBM signalosome assembly and MALT1 phosphorylation. MALT1 phosphorylation is largely dispensable for protease activity but fosters canonical NF-κB signaling and promotes survival of ABC-DLBCL cells.","method":"Unbiased mass spectrometry phosphoproteomics, phospho-specific antibody generation, CK1α kinase assays, genetic and pharmacological CK1α inhibition, Jurkat/primary CD4 T cell NF-κB assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — mass spectrometry discovery plus kinase identification plus functional validation","pmids":["31644910"],"is_preprint":false},{"year":2019,"finding":"An allosteric MALT1 inhibitor binds by displacing the side chain of Trp580, locking the protease in an inactive conformation. Loss of Trp580 (W580S patient mutation) weakens interactions between the paracaspase and C-terminal Ig-like domains causing protein instability; allosteric inhibitor binding rescues W580S MALT1 stability and restores NF-κB/JNK signaling in patient lymphocytes.","method":"Structural analysis of inhibitor binding mode, biochemical protein stability assays, patient lymphocyte NF-κB/JNK signaling assays, MALT1 substrate cleavage recovery after compound washout","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — structural mechanism defined with patient cell functional validation","pmids":["30692685"],"is_preprint":false},{"year":2003,"finding":"The API2-MALT1 fusion protein is stable compared to wild-type MALT1 (which is rapidly degraded via the ubiquitin-proteasome pathway). Both MALT1 and API2-MALT1 are localized exclusively in the cytoplasm.","method":"Subcellular fractionation, Western blot stability assays, proteasome inhibitor treatment, deletion mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization and stability experiments, single lab","pmids":["14603249"],"is_preprint":false},{"year":2022,"finding":"hnRNP U and hnRNP L competitively bind stem-loop RNA structures flanking MALT1 exon7. hnRNP U stabilizes RNA stem-loop conformations maintaining exon7 skipping (MALT1B), while hnRNP L disrupts these elements to recruit splicing factor U2AF2 and promote exon7 inclusion (MALT1A).","method":"NMR structure of RNA stem-loops, RNA-protein binding assays, competitive binding studies, splicing reporter assays, U2AF2 recruitment analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — NMR structure of regulatory RNA elements plus biochemical competitive binding and functional splicing assays","pmids":["35921415"],"is_preprint":false},{"year":2015,"finding":"MALT1 is required for EGFR-induced NF-κB activation in cancer cells, functioning mainly as a scaffold protein by recruiting TRAF6 to the IKK complex. MALT1 deficiency abolished both NF-κB and STAT3 activation in EGFR-driven lung tumors in vivo, attributed to defective IL-6 production.","method":"MALT1 knockdown in cancer cells, triple-transgenic EGFR-driven lung cancer mouse model (Malt1-/-), NF-κB/STAT3 activation assays, IL-6 production measurement, tumor burden analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with mechanistic pathway analysis","pmids":["25982276"],"is_preprint":false},{"year":2022,"finding":"Gab2 facilitates assembly of the CARMA3-BCL10-MALT1 signalosome in endothelial cells. MALT1 within this complex mediates IL-1β-induced Rho-dependent exocytosis of P-selectin and von Willebrand factor, NF-κB-dependent tissue factor expression, and neutrophil adhesion. MALT1 inhibition or Gab2 silencing suppresses venous thrombosis in mice.","method":"Gene silencing (Gab2, MALT1), MALT1 pharmacological inhibition (mepazine), P-selectin/VWF exocytosis assays, Rho activity assays, inferior vena cava ligation DVT mouse model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic and pharmacological evidence in vitro and in vivo, single lab","pmids":["35895897"],"is_preprint":false},{"year":2021,"finding":"TRAF6 recruits to MALT1 in activated T cells and is indispensable for NF-κB signaling, but also counteracts basal MALT1 protease activity in resting T cells via a homeostatic suppression mechanism. Loss of this suppression leads to fatal autoimmune inflammation fully reversed by MALT1 protease inactivation.","method":"T cell-conditional TRAF6 knockout mice, MALT1 protease activity measurement in resting vs. activated T cells, MALT1 protease-dead genetic rescue, pharmacological MALT1 inhibitor treatment","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional genetic models with biochemical MALT1 activity assays and full phenotypic rescue","pmids":["34767456"],"is_preprint":false},{"year":2021,"finding":"Keratinocyte-intrinsic BCL10/MALT1 signaling amplifies responses to IL-17A, IL-1β, and TNF and is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation. Selective keratinocyte BCL10/MALT1 deletion completely rescues Card14 gain-of-function-driven skin pathology.","method":"Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function mouse model, artificial BCL10/MALT1 activating engager molecule, cytokine response assays, skin inflammation scoring","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional genetic models with gain-of-function and loss-of-function validation","pmids":["34826258"],"is_preprint":false}],"current_model":"MALT1 is a paracaspase that functions as both a scaffolding protein and an arginine-specific protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome: upon antigen receptor or GPCR stimulation, MALT1 is polyubiquitinated (K63-linked, by TRAF6) and dimerizes, enabling it to recruit NEMO/IKKγ for canonical NF-κB activation, while its protease activity cleaves and inactivates negative regulators of NF-κB (A20, CYLD, RelB, HOIL1) and other substrates (N4BP1, c-Jun), thereby amplifying and sustaining inflammatory gene expression; MALT1 protease activity is additionally regulated by CK1α-mediated phosphorylation, TRAF6-mediated homeostatic suppression in resting T cells, and alternative splicing that controls TRAF6 recruitment, and its constitutive activation in ABC-DLBCL and other malignancies drives lymphoma survival and proliferation."},"narrative":{"teleology":[{"year":2003,"claim":"Early characterization established that MALT1 is a cytoplasmic protein subject to rapid proteasomal turnover, whereas the oncogenic API2-MALT1 fusion escapes degradation—raising the question of how MALT1 stability is regulated and how the fusion contributes to lymphomagenesis.","evidence":"Subcellular fractionation, proteasome inhibitor treatment, and Western blot stability assays in overexpression systems","pmids":["14603249"],"confidence":"Medium","gaps":["Single lab, no endogenous protein analysis","Mechanism of proteasomal targeting not identified","No functional consequence of stabilization tested"]},{"year":2005,"claim":"Discovery of nuclear export signals in MALT1 revealed that it undergoes constitutive nucleocytoplasmic shuttling and actively maintains BCL10 in the cytoplasm, establishing that MALT1 has a localization-regulatory role beyond signal transduction.","evidence":"Deletion mutants, leptomycin B (NES inhibitor) treatment, and cellular fractionation","pmids":["16123224"],"confidence":"Medium","gaps":["Single lab observation","Functional significance of nuclear shuttling for NF-κB signaling not resolved","Endogenous protein shuttling not tracked"]},{"year":2006,"claim":"The CBM complex was shown to operate beyond lymphocytes: BCL10 and MALT1 are essential and selective mediators of GPCR-induced NF-κB activation in non-immune cells (fibroblasts, hepatocytes), establishing MALT1 as a broadly utilized NF-κB signaling node.","evidence":"Bcl10−/− and Malt1−/− MEFs and dominant-negative mutants with NF-κB pathway-selective readouts for LPA and angiotensin II stimulation","pmids":["17101977","17095601"],"confidence":"High","gaps":["Upstream mechanism linking GPCRs to CBM assembly not defined","Whether MALT1 protease activity is engaged downstream of GPCRs was untested"]},{"year":2007,"claim":"The molecular mechanism linking MALT1 to IKK was resolved: TRAF6-mediated K63-linked polyubiquitination of MALT1 C-terminal lysines creates a docking platform for NEMO/IKKγ, directly connecting CBM assembly to IKK activation.","evidence":"In vitro ubiquitination with recombinant TRAF6, Malt1−/− T cell reconstitution with lysine mutants, IL-2 production","pmids":["17948050"],"confidence":"High","gaps":["Stoichiometry and dynamics of NEMO recruitment not determined","Whether other E3 ligases contribute was unknown"]},{"year":2007,"claim":"In B cells, MALT1 was found to selectively activate c-Rel without being required for IKK activation or RelA induction, revealing that MALT1 controls a specific NF-κB transcriptional subprogram rather than acting as a generic IKK activator.","evidence":"Malt1−/− B cells with NF-κB subunit-specific DNA-binding and survival assays","pmids":["17660823"],"confidence":"High","gaps":["Mechanism of c-Rel selectivity not determined","Whether this selectivity extends to T cells was untested"]},{"year":2008,"claim":"MALT1 was identified as an active protease (paracaspase) that cleaves A20 after Arg-439, removing a key NF-κB negative regulator and establishing the paradigm of MALT1 protease-mediated amplification of NF-κB signaling.","evidence":"In vitro cleavage assay, R439 mutagenesis, co-IP of A20 into BCL10-MALT1 complex, NF-κB reporter assays","pmids":["18223652"],"confidence":"High","gaps":["Full substrate repertoire unknown","Whether protease activity is essential in vivo was untested"]},{"year":2009,"claim":"A reciprocal regulatory circuit was established: A20 deubiquitinates K63-linked chains on MALT1 to limit IKK recruitment, while MALT1 protease cleaves A20, creating a feedback loop that controls NF-κB signaling duration.","evidence":"Malt1−/− T cell reconstitution, ubiquitin chain analysis, IKK activity assays","pmids":["19494296"],"confidence":"High","gaps":["Temporal dynamics of this feedback in vivo not resolved","Whether other DUBs target MALT1 was unknown"]},{"year":2009,"claim":"MALT1 was shown to participate in non-canonical NF-κB signaling: it is required for BAFF-induced p100 processing and RelB nuclear translocation in marginal zone B cells, interacting with TRAF3 to modulate its levels.","evidence":"Malt1−/− B cells, MALT1-TRAF3 co-IP, NF-κB2 processing assays, BAFF-overexpression in vivo model","pmids":["19917778"],"confidence":"High","gaps":["Whether MALT1 protease activity is required for non-canonical signaling was unclear","Mechanism of TRAF3 level regulation by MALT1 not defined"]},{"year":2011,"claim":"The substrate repertoire of MALT1 protease expanded to include CYLD (enabling JNK activation) and RelB (enabling canonical NF-κB DNA binding by removing an inhibitory competitor), demonstrating that MALT1 cleavage of multiple negative regulators coordinates NF-κB and JNK pathway activation.","evidence":"In vitro cleavage assays with mutagenesis, Malt1−/− reconstitution, JNK assays, NF-κB DNA-binding assays, DLBCL survival assays","pmids":["21448133","21873235"],"confidence":"High","gaps":["Relative contribution of each substrate cleavage to NF-κB output not quantified","In vivo physiological significance of individual cleavage events untested"]},{"year":2012,"claim":"Structural and biochemical studies established that MALT1 protease activity depends on dimerization (not autocleavage), with arginine-directed specificity and kinetics comparable to caspases, and that the C-terminal Ig-like domain is essential for activity.","evidence":"Crystal structure, dimer interface mutagenesis, positional-scanning substrate libraries, kinetic measurements of CYLD cleavage","pmids":["22366302","22309193"],"confidence":"High","gaps":["Full-length MALT1 structure with BCL10 not available","Mechanism of activation at the CBM level not structurally resolved"]},{"year":2014,"claim":"MALT1 auto-proteolysis after Arg-149 was identified as a post-activation event that does not regulate catalytic activity per se but is required for optimal NF-κB-dependent transcription, and p62 was found to scaffold the BCL10-MALT1-IKK signalosome in the cytosol.","evidence":"R149A mutagenesis with transcriptome analysis in Jurkat T cells; p62−/− T cells with confocal imaging of signalosome assembly","pmids":["25105596","24825920"],"confidence":"High","gaps":["How autocleavage enhances transcription mechanistically is unknown","Whether p62 scaffolding is cell-type specific was untested"]},{"year":2015,"claim":"MALT1 protease-dead knock-in mice revealed that protease activity is essential in vivo for marginal zone/B1 B cell development, T cell proliferation, dendritic cell innate responses, and immune homeostasis, while its scaffolding function alone is insufficient.","evidence":"MALT1 protease-dead knock-in mouse with comprehensive flow cytometry, proliferation assays, immunization, and dendritic cell cytokine assays","pmids":["25665967"],"confidence":"High","gaps":["Relative contribution of individual substrate cleavages to each phenotype not dissected","Whether protease-dead mice develop lymphoma or autoimmunity long-term was not fully characterized"]},{"year":2015,"claim":"MALT1 was established as a key effector of EGFR-driven oncogenic signaling: it scaffolds TRAF6 recruitment to IKK for NF-κB/STAT3 activation and IL-6 production in EGFR-driven lung tumors, demonstrating CBM pathway cooption by receptor tyrosine kinases in cancer.","evidence":"MALT1 knockdown in cancer cells, Malt1−/− triple-transgenic EGFR-driven lung cancer mouse model, tumor burden analysis","pmids":["25982276"],"confidence":"High","gaps":["Whether MALT1 protease vs. scaffold function drives lung tumorigenesis not separated","Applicability to other RTK-driven cancers untested"]},{"year":2016,"claim":"Alternative splicing was shown to control MALT1 scaffolding: the MALT1A isoform (exon7-included) facilitates TRAF6 recruitment without altering protease activity, and TCR stimulation induces exon7 inclusion via hnRNP U regulation, adding a splicing-based regulatory layer to CBM signaling.","evidence":"Isoform-selective knockdown, TRAF6 co-IP, hnRNP U knockdown, splicing reporters, T cell activation assays","pmids":["27068814"],"confidence":"High","gaps":["Whether MALT1A/B ratio is dysregulated in disease was not determined","How TCR stimulation modulates hnRNP U activity was unclear"]},{"year":2016,"claim":"MALT1 substrate repertoire expanded further: HOIL1 (LUBAC subunit) cleavage removes linear ubiquitin chain-generating capacity to amplify NF-κB, and CARD14 was identified as a MALT1 activator in keratinocytes with psoriasis-associated gain-of-function mutations constitutively driving MALT1 protease activity.","evidence":"In vitro cleavage assays, cleavage-resistant HOIL1 rescue, CARD14-MALT1 co-IP and protease activity in primary keratinocytes","pmids":["27006117","27113748"],"confidence":"High","gaps":["Whether HOIL1 cleavage contributes to ABC-DLBCL pathogenesis in patients was untested","Full spectrum of CARD14-MALT1 substrates in keratinocytes unknown"]},{"year":2018,"claim":"Cryo-EM revealed the structural basis for CBM signalosome assembly: CARMA1-nucleated BCL10 CARD filaments serve as a template for cooperative MALT1 dimerization and subsequent TRAF6 decoration, explaining the switch-like, all-or-none NF-κB activation behavior.","evidence":"4.0-Å cryo-EM of BCL10 filament, negative-stain EM of CBM-TRAF6, time-lapse confocal imaging","pmids":["29382759"],"confidence":"High","gaps":["Full atomic-resolution structure of MALT1 on the filament not achieved","How filament disassembly/termination occurs is unknown"]},{"year":2019,"claim":"Multiple regulatory inputs and functional outputs of MALT1 were defined: CK1α phosphorylates MALT1 C-terminal serines to enhance NF-κB signaling; HECTD3-mediated K27/K29-linked ubiquitination at K648 promotes NF-κB and Th17 differentiation; MALT1 cleaves N4BP1 to relieve HIV-1 latency; and MALT1 protease activity is essential for Treg suppressive function and tumor immune evasion.","evidence":"Mass spectrometry phosphoproteomics with CK1α kinase assays; Hectd3−/− mice with linkage-specific ubiquitination; N4BP1 cleavage assay with HIV-1 reactivation; conditional BCL10 knockout and MALT1 protease-dead mice in melanoma models","pmids":["31644910","30741923","31133753","31138793"],"confidence":"High","gaps":["Integration of phosphorylation and ubiquitination signals on MALT1 not resolved","Whether N4BP1 cleavage is relevant beyond HIV latency reversal unknown","Therapeutic window for MALT1 inhibition in cancer immunotherapy not defined"]},{"year":2019,"claim":"Structural pharmacology of MALT1 was advanced: an allosteric inhibitor locks the protease inactive by displacing Trp580, and this same mechanism rescues the destabilizing W580S patient mutation, demonstrating that allosteric regulation couples protease domain conformation to Ig-like domain interactions.","evidence":"Structural analysis of inhibitor binding, protein stability assays, patient lymphocyte NF-κB/JNK signaling recovery","pmids":["30692685"],"confidence":"High","gaps":["Whether allosteric inhibitors are effective in vivo in disease models not shown in this study","Full landscape of loss-of-function MALT1 mutations in immunodeficiency not mapped"]},{"year":2020,"claim":"MALT1 protease was linked to metabolic reprogramming in Th17 cells: it stabilizes c-Jun by cleavage, promoting GLS1 expression and glutaminolysis that drives H3 acetylation at the Il17a promoter and Th17/γδT17 differentiation in psoriasis.","evidence":"MALT1 inhibitor, c-Jun cleavage assay, ChIP for H3 acetylation, GLS1 analysis, mouse psoriasis models","pmids":["32831293"],"confidence":"Medium","gaps":["Single lab study","Whether metabolic reprogramming by MALT1 extends beyond Th17 cells untested","Direct protease cleavage site on c-Jun not mapped"]},{"year":2021,"claim":"TRAF6 was revealed to have a dual role: beyond activating NF-κB through MALT1 ubiquitination, TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells, and loss of this suppression causes fatal autoimmunity fully rescued by MALT1 protease inactivation.","evidence":"T cell-conditional TRAF6 knockout mice, MALT1 protease measurement in resting vs. activated cells, genetic protease-dead rescue, pharmacological MALT1 inhibitor","pmids":["34767456"],"confidence":"High","gaps":["Molecular mechanism of TRAF6-mediated protease suppression not defined","Whether other ubiquitin ligases contribute to basal MALT1 suppression unknown"]},{"year":2021,"claim":"Keratinocyte-intrinsic BCL10/MALT1 signaling was established as a driver of psoriasiform inflammation: it amplifies IL-17A/IL-1β/TNF responses and is necessary and sufficient for CARD14 gain-of-function-driven skin disease.","evidence":"Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function model, artificial CBM activating molecules","pmids":["34826258"],"confidence":"High","gaps":["Whether MALT1 protease vs. scaffold function drives skin inflammation not separated","Therapeutic efficacy of MALT1 inhibitors in psoriasis patients unknown"]},{"year":2022,"claim":"The RNA structural basis of MALT1 alternative splicing was resolved: hnRNP U and hnRNP L competitively bind stem-loop structures flanking exon7, with hnRNP L disrupting these elements to recruit U2AF2 and promote MALT1A expression.","evidence":"NMR structure of regulatory RNA stem-loops, competitive RNA-protein binding assays, splicing reporter assays","pmids":["35921415"],"confidence":"High","gaps":["How TCR activation shifts the hnRNP U/L balance mechanistically remains unknown","Whether splicing dysregulation contributes to MALT1-dependent malignancies untested"]},{"year":2022,"claim":"MALT1 function was extended to endothelial cells: Gab2 facilitates CARMA3-BCL10-MALT1 assembly to mediate IL-1β-induced Rho-dependent exocytosis and NF-κB-driven tissue factor expression, contributing to venous thrombosis.","evidence":"Gab2/MALT1 silencing, pharmacological MALT1 inhibition, P-selectin/VWF exocytosis, IVC ligation DVT mouse model","pmids":["35895897"],"confidence":"Medium","gaps":["Single lab finding","Whether MALT1 protease or scaffold function mediates thrombotic phenotype not resolved","Relevance to human venous thromboembolism unknown"]},{"year":null,"claim":"Key unresolved questions include the full atomic structure of MALT1 within the assembled CBM filament, the molecular mechanism by which TRAF6 suppresses basal MALT1 protease activity, the complete inventory of MALT1 substrates across cell types, and whether selective MALT1 protease inhibitors can be therapeutically deployed in autoimmunity and cancer without unacceptable immunosuppression.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length MALT1-on-filament atomic structure","TRAF6 suppression mechanism molecularly undefined","Therapeutic index of MALT1 inhibition in patients unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,6,7,13,15,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9,12,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,15,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23,27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,9,10,11,25,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,11,14,21,22,31,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,15,25,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,24,25]}],"complexes":["CBM signalosome (CARMA/CARD-BCL10-MALT1)","BCL10-MALT1 complex"],"partners":["BCL10","TRAF6","CARD11","CARD14","CARD10","NEMO","TRAF3","SQSTM1"],"other_free_text":[]},"mechanistic_narrative":"MALT1 is a paracaspase that functions as both a scaffold and an arginine-specific cysteine protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome, serving as a central integrator of NF-κB activation downstream of antigen receptors, GPCRs, and innate immune receptors in lymphocytes, keratinocytes, and other cell types [PMID:17948050, PMID:17101977, PMID:27113748]. As a scaffold, MALT1 undergoes TRAF6-mediated K63-linked polyubiquitination that recruits NEMO/IKKγ for IKK activation, and BCL10 filament-templated MALT1 dimerization cooperatively assembles higher-order signalosomes with TRAF6 for switch-like NF-κB responses; alternative splicing (MALT1A/B) and CK1α-mediated phosphorylation further tune scaffold output [PMID:17948050, PMID:29382759, PMID:27068814, PMID:31644910]. Dimerization-dependent protease activity cleaves and inactivates negative regulators of NF-κB—including A20, CYLD, RelB, and HOIL1—after arginine residues, amplifying canonical NF-κB and JNK signaling, while TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells to prevent autoimmunity [PMID:18223652, PMID:21448133, PMID:21873235, PMID:27006117, PMID:34767456]. MALT1 protease activity is required for regulatory T cell suppressive function, Th17 differentiation, marginal zone B cell development, and contributes to oncogenic NF-κB in ABC-DLBCL; in keratinocytes, CBM signaling downstream of psoriasis-associated CARD14 mutations drives psoriasiform inflammation [PMID:31138793, PMID:25665967, PMID:34826258]."},"prefetch_data":{"uniprot":{"accession":"Q9UDY8","full_name":"Mucosa-associated lymphoid tissue lymphoma translocation protein 1","aliases":["MALT lymphoma-associated translocation","Paracaspase"],"length_aa":824,"mass_kda":92.3,"function":"Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:11262391, PubMed:18264101, PubMed:24074955). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (PubMed:11262391, PubMed:18264101). Involved in the induction of T helper 17 cells (Th17) differentiation (PubMed:11262391, PubMed:18264101). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation (PubMed:31133753). May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (PubMed:14695475)","subcellular_location":"Cytoplasm, perinuclear region; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UDY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MALT1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MALT1","total_profiled":1310},"omim":[{"mim_id":"619138","title":"NEDD4-BINDING PROTEIN 1; N4BP1","url":"https://www.omim.org/entry/619138"},{"mim_id":"618638","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 3; HECTD3","url":"https://www.omim.org/entry/618638"},{"mim_id":"615468","title":"IMMUNODEFICIENCY 12; IMD12","url":"https://www.omim.org/entry/615468"},{"mim_id":"610694","title":"PYROGLUTAMYL PEPTIDASE I; PGPEP1","url":"https://www.omim.org/entry/610694"},{"mim_id":"610562","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12A; ZC3H12A","url":"https://www.omim.org/entry/610562"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":19.0}],"url":"https://www.proteinatlas.org/search/MALT1"},"hgnc":{"alias_symbol":["PCASP1"],"prev_symbol":["MLT"]},"alphafold":{"accession":"Q9UDY8","domains":[{"cath_id":"1.10.533.10","chopping":"31-123","consensus_level":"high","plddt":88.588,"start":31,"end":123},{"cath_id":"2.60.40.10","chopping":"128-210","consensus_level":"medium","plddt":90.9729,"start":128,"end":210},{"cath_id":"2.60.40.10","chopping":"214-309","consensus_level":"medium","plddt":88.1939,"start":214,"end":309},{"cath_id":"3.40.50.1460","chopping":"343-582","consensus_level":"high","plddt":91.2942,"start":343,"end":582},{"cath_id":"2.60.40.3360","chopping":"585-716","consensus_level":"high","plddt":93.8001,"start":585,"end":716}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UDY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UDY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UDY8-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MALT1","jax_strain_url":"https://www.jax.org/strain/search?query=MALT1"},"sequence":{"accession":"Q9UDY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UDY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UDY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UDY8"}},"corpus_meta":[{"pmid":"18223652","id":"PMC_18223652","title":"T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20.","date":"2008","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18223652","citation_count":371,"is_preprint":false},{"pmid":"19494296","id":"PMC_19494296","title":"A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19494296","citation_count":200,"is_preprint":false},{"pmid":"20685844","id":"PMC_20685844","title":"Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1.","date":"2010","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/20685844","citation_count":193,"is_preprint":false},{"pmid":"21873235","id":"PMC_21873235","title":"Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21873235","citation_count":190,"is_preprint":false},{"pmid":"21448133","id":"PMC_21448133","title":"T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21448133","citation_count":183,"is_preprint":false},{"pmid":"17948050","id":"PMC_17948050","title":"Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17948050","citation_count":177,"is_preprint":false},{"pmid":"30467369","id":"PMC_30467369","title":"CARD-BCL-10-MALT1 signalling in protective and pathological immunity.","date":"2019","source":"Nature reviews. 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API2-MALT1 fusion likewise cleaves A20.\",\n      \"method\": \"Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis (R439 cleavage site identification), cell-based NF-κB reporter assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assay with mutagenesis, replicated in multiple cell systems\",\n      \"pmids\": [\"18223652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A20 functions as a deubiquitinating enzyme for MALT1, removing K63-linked ubiquitin chains from MALT1 to prevent sustained IKK complex recruitment and limit NF-κB signaling duration after TCR/CD28 stimulation. Reciprocally, MALT1 paracaspase activity cleaves and inactivates A20.\",\n      \"method\": \"Malt1-/- T cell reconstitution, antagonistic peptides, ubiquitin chain analysis, IKK activity assays, IL-2 production measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic reconstitution plus biochemical ubiquitin assays with multiple orthogonal methods\",\n      \"pmids\": [\"19494296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRAF6 associates with MALT1 upon T cell activation and mediates K63-linked polyubiquitination of MALT1 at multiple C-terminal lysine residues. These ubiquitin chains serve as a docking surface for NEMO/IKKγ recruitment, linking CBM complex formation to IKK/NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay with TRAF6 as E3, Malt1-/- T cell reconstitution with ubiquitin-acceptor lysine mutants, IL-2 production readout\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of ubiquitination plus genetic rescue in knockout cells\",\n      \"pmids\": [\"17948050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MALT1 proteolytically inactivates CYLD, which is required for TCR-induced JNK activation and expression of a subset of JNK-dependent genes. This cleavage is also induced by the oncogenic API2-MALT1 fusion.\",\n      \"method\": \"In vitro cleavage assay, Malt1-/- cell reconstitution, JNK activation assays, gene expression profiling, paracaspase inhibitor treatment\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro cleavage demonstrated, genetic and pharmacological validation with defined phenotypic readout\",\n      \"pmids\": [\"21448133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MALT1 cleaves the NF-κB family member RelB after Arg-85, inducing its proteasomal degradation and specifically enabling DNA binding of RelA- and c-Rel-containing NF-κB complexes to drive canonical NF-κB target gene expression.\",\n      \"method\": \"In vitro cleavage assay, site-directed mutagenesis (R85 site), proteasome inhibitor studies, NF-κB DNA-binding assays, DLBCL cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assay with mutagenesis plus functional cellular validation\",\n      \"pmids\": [\"21873235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MALT1 protease activity is dependent on dimerization; the unliganded protease exists as a dimer in an inactive state and undergoes substantial conformational changes upon substrate binding. The C-terminal Ig-like domain is required for MALT1 activity. Dimer interface mutations abrogate protease activity in cells.\",\n      \"method\": \"Crystal structure determination, biochemical dimerization assays, mutagenesis of dimer interface, cell-based protease activity assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus functional validation in cells\",\n      \"pmids\": [\"22366302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MALT1 paracaspase cleaves specifically after arginine residues with stringent peptide length constraints. Dimerization activates both full-length MALT1 and its catalytic domain without cleavage, analogous to apical caspases. CYLD is cleaved by MALT1 with kcat/Km values comparable to optimal peptidyl substrates.\",\n      \"method\": \"Positional-scanning peptidyl substrate libraries, recombinant protein expression and purification, in vitro kinetic assays, dimerization studies\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with substrate library profiling and kinetic measurements\",\n      \"pmids\": [\"22309193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MALT1 undergoes auto-proteolytic cleavage after Arg-149 (between the death domain and first Ig-like region) upon antigen receptor stimulation. This autocleavage does not affect protease activity but is required for optimal NF-κB-dependent transcription of target genes (IL-2, CSF2) downstream of nuclear NF-κB accumulation.\",\n      \"method\": \"Site-directed mutagenesis (R149A), Jurkat T cell reconstitution, NF-κB reporter assays, transcriptome analysis, IκBα phosphorylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with transcriptome validation and multiple functional readouts\",\n      \"pmids\": [\"25105596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of BCL10 CARD filament at 4.0-Å resolution shows CARMA1 nucleates unidirectional BCL10 polymerization. MALT1 cooperatively interacts with BCL10 filaments and immediately dimerizes on the filamentous scaffold. TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies for all-or-none downstream pathway activation.\",\n      \"method\": \"Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, pulldown assays, negative-stain EM\",\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 with live imaging and biochemical validation\",\n      \"pmids\": [\"29382759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARMA3-BCL10-MALT1 mediates angiotensin II receptor (GPCR)-induced NF-κB activation in non-immune hepatocytes, acting through IKKγ ubiquitination. Dominant-negative mutants, RNAi, or gene targeting of any CBM component abolishes Ang II-dependent NF-κB activation.\",\n      \"method\": \"Dominant-negative mutants, RNAi knockdown, Bcl10-/- mouse embryonic fibroblasts, NF-κB reporter assays, cytokine production measurement in vivo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple loss-of-function approaches with in vitro and in vivo validation\",\n      \"pmids\": [\"17101977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCL10 and MALT1 are essential mediators of lysophosphatidic acid (LPA)-induced NF-κB activation downstream of G protein-coupled receptors in non-immune fibroblasts, cooperating with PKCs selectively for NF-κB but dispensable for JNK, p38, ERK, and Akt pathways.\",\n      \"method\": \"Bcl10-/- and Malt1-/- mouse embryonic fibroblasts, IκBα degradation assays, NF-κB activation assays, kinase pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with pathway-selective functional analysis\",\n      \"pmids\": [\"17095601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MALT1 selectively activates c-Rel but not RelA in B cells after BCR stimulation. MALT1 participates in survival signaling but is not required for IKK recruitment into lipid rafts, IKK activation, or RelA induction, demonstrating selective control of a c-Rel-dependent transcriptional subprogram.\",\n      \"method\": \"Malt1-/- B cells, lipid raft fractionation, NF-κB subunit-specific assays, cell survival and proliferation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with subunit-resolved mechanistic analysis\",\n      \"pmids\": [\"17660823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MALT1 alternative splicing generates two conserved isoforms: MALT1A (exon7-included) and MALT1B. MALT1A facilitates TRAF6 recruitment, augmenting MALT1 scaffolding function but not protease activity. hnRNP U suppresses exon7 inclusion; TCR stimulation induces MALT1A expression. Selective MALT1A depletion impairs T cell signaling and activation.\",\n      \"method\": \"Isoform-selective knockdown, Co-immunoprecipitation of TRAF6, NF-κB signaling assays, hnRNP U knockdown, T cell activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-selective manipulation with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"27068814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 proteolytically cleaves N4BP1 (an HIV-1 restriction factor with RNase activity) at Arg-509 upon T cell activation, inactivating N4BP1's ability to degrade viral mRNA and thereby facilitating reactivation of latent HIV-1 proviruses.\",\n      \"method\": \"RNA-binding protein screen, N4BP1 cleavage assay, MALT1 knockout/knockdown studies, HIV-1 reactivation assay, mutational analysis of cleavage site\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cleavage site identified by mutagenesis, knockout validation, and functional viral reactivation readout\",\n      \"pmids\": [\"31133753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARD14 physically interacts with MALT1 and activates MALT1 proteolytic activity in keratinocytes. Psoriasis-associated CARD14 mutations enhance this interaction constitutively, driving BCL10- and MALT1-dependent NF-κB, p38, and JNK activation, and inflammatory gene expression.\",\n      \"method\": \"Co-immunoprecipitation, MALT1 protease activity assays, MALT1 siRNA/inhibitor studies, primary human keratinocyte assays with psoriasis-mutant CARD14\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction demonstrated, protease activity measured, pharmacological and genetic validation\",\n      \"pmids\": [\"27113748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MALT1 cleaves the LUBAC subunit HOIL1 upon antigen receptor engagement. HOIL1 is constitutively processed in ABC-DLBCL cells with aberrant MALT1 activity. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, identifying HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1.\",\n      \"method\": \"In vitro cleavage assay, MALT1 inhibitor treatment, overexpression of cleavage-resistant HOIL1 mutant, NF-κB reporter assay, cytokine measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro cleavage plus cleavage-resistant mutant functional rescue\",\n      \"pmids\": [\"27006117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MALT1 contains nuclear export signal (NES) sequences in its C-terminal region, causing constitutive nucleocytoplasmic shuttling. MALT1 regulates cytoplasmic localization of BCL10 through this NES-dependent export mechanism.\",\n      \"method\": \"Deletion mutant analysis, leptomycin B treatment (NES inhibitor), cellular fractionation and localization studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with pharmacological validation, but single lab\",\n      \"pmids\": [\"16123224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MALT1 is required for BAFF-induced non-canonical NF-κB signaling (phosphorylation of NF-κB2/p100, p100 degradation, RelB nuclear translocation) in marginal zone B cells. MALT1 interacts with TRAF3, a negative regulator of BAFF receptor signaling, and MALT1 deficiency results in elevated TRAF3 levels.\",\n      \"method\": \"Malt1-/- B cells, Co-immunoprecipitation (MALT1-TRAF3), NF-κB2 processing assays, B cell survival assays, in vivo BAFF-overexpression model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with mechanistic Co-IP and multiple functional readouts in vitro and in vivo\",\n      \"pmids\": [\"19917778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BCL10-MALT1 interaction involves multiple protein domains: the Ig-like domains of MALT1 interact with a post-CARD region of BCL10, but the MALT1 death domain and BCL10 CARD also contribute. FRET analysis identified the MALT1 death domain contribution in live T cells. BCL10 CARD residues Asp80 and Glu84 in helix 5 directly contact MALT1.\",\n      \"method\": \"Co-immunoprecipitation, FRET analysis in T cells, BCL10 point mutant analysis, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus FRET plus mutagenesis, single lab\",\n      \"pmids\": [\"18806265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF6 plays a dual role: it recruits to MALT1 for NF-κB signaling in activated T cells, but also counteracts basal MALT1 protease activity in resting T cells. Loss of TRAF6-mediated homeostatic suppression leads to severe autoimmune inflammation fully rescued by MALT1 protease inactivation.\",\n      \"method\": \"Genetically engineered mouse models (T cell-specific TRAF6 knockout), biochemical MALT1 protease activity assays, pharmacological MALT1 inhibitor rescue, autoimmune phenotype analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic models with biochemical validation and therapeutic rescue\",\n      \"pmids\": [\"34767456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 protease is constitutively active in psoriatic CD4+ and γδ T cells and stabilizes c-Jun by proteolytic cleavage, thereby supporting GLS1 (glutaminase 1) expression. This promotes glutaminolysis, H3 acetylation at the Il17a promoter, and Th17/γδT17 cell differentiation contributing to psoriasis.\",\n      \"method\": \"MALT1 inhibitor treatment, c-Jun cleavage assay, chromatin immunoprecipitation (H3 acetylation), GLS1 expression analysis, mouse psoriasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological inhibition plus chromatin analysis, single lab\",\n      \"pmids\": [\"32831293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BCL10-controlled MALT1 paracaspase activity is essential for the immune-suppressive function of regulatory T cells (Tregs) but not for their differentiation per se. In tumor models, acute genetic BCL10 blockade in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses.\",\n      \"method\": \"T cell-conditional BCL10 knockout mice, MALT1 protease-dead knock-in mice, melanoma mouse models, Treg suppression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic models with defined functional readout, replicated pharmacologically\",\n      \"pmids\": [\"31138793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MALT1 protease-dead knock-in mice reveal that MALT1 protease activity is required for marginal zone and B1 B cell development, T cell proliferation and IL-2 production, dendritic cell cytokine responses to Dectin-1/2/Mincle, and immune homeostasis. Protease-dead mice develop mixed inflammatory cell infiltrates in multiple organs.\",\n      \"method\": \"MALT1 protease-dead knock-in mouse generation, flow cytometry of lymphocyte subsets, proliferation assays, in vivo immunization, dendritic cell cytokine assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse with comprehensive immune phenotyping across multiple cell types\",\n      \"pmids\": [\"25665967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TCR signals to NF-κB are transmitted through a cytosolic p62-BCL10-MALT1-IKK signalosome. p62 is required for clustering of BCL10-MALT1 with IKK in effector T cells. TAK1 and IKK inhibition block IKK phosphorylation but not signalosome assembly, indicating IKK activation occurs after signalosome formation.\",\n      \"method\": \"Confocal imaging of signalosome assembly, p62-/- T cells, kinase inhibitor studies, co-immunoprecipitation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic knockout with imaging and biochemical validation, single lab\",\n      \"pmids\": [\"24825920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The E3 ubiquitin ligase HECTD3 promotes K27-linked and K29-linked non-degradative polyubiquitination of MALT1 at K648, which is required for NF-κB activation and Th17 cell differentiation in experimental autoimmune encephalomyelitis.\",\n      \"method\": \"Hectd3-/- mice, ubiquitination assays with linkage-specific antibodies, Malt1 K648 mutagenesis, NF-κB activation assays, Th17 differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with site-specific mutagenesis and functional validation\",\n      \"pmids\": [\"30741923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 phosphorylation at multiple C-terminal serine residues occurs after TCR/CD28 co-stimulation, mediated by CK1α. CK1α is essential for both CBM signalosome assembly and MALT1 phosphorylation. MALT1 phosphorylation is largely dispensable for protease activity but fosters canonical NF-κB signaling and promotes survival of ABC-DLBCL cells.\",\n      \"method\": \"Unbiased mass spectrometry phosphoproteomics, phospho-specific antibody generation, CK1α kinase assays, genetic and pharmacological CK1α inhibition, Jurkat/primary CD4 T cell NF-κB assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry discovery plus kinase identification plus functional validation\",\n      \"pmids\": [\"31644910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An allosteric MALT1 inhibitor binds by displacing the side chain of Trp580, locking the protease in an inactive conformation. Loss of Trp580 (W580S patient mutation) weakens interactions between the paracaspase and C-terminal Ig-like domains causing protein instability; allosteric inhibitor binding rescues W580S MALT1 stability and restores NF-κB/JNK signaling in patient lymphocytes.\",\n      \"method\": \"Structural analysis of inhibitor binding mode, biochemical protein stability assays, patient lymphocyte NF-κB/JNK signaling assays, MALT1 substrate cleavage recovery after compound washout\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural mechanism defined with patient cell functional validation\",\n      \"pmids\": [\"30692685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The API2-MALT1 fusion protein is stable compared to wild-type MALT1 (which is rapidly degraded via the ubiquitin-proteasome pathway). Both MALT1 and API2-MALT1 are localized exclusively in the cytoplasm.\",\n      \"method\": \"Subcellular fractionation, Western blot stability assays, proteasome inhibitor treatment, deletion mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization and stability experiments, single lab\",\n      \"pmids\": [\"14603249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNP U and hnRNP L competitively bind stem-loop RNA structures flanking MALT1 exon7. hnRNP U stabilizes RNA stem-loop conformations maintaining exon7 skipping (MALT1B), while hnRNP L disrupts these elements to recruit splicing factor U2AF2 and promote exon7 inclusion (MALT1A).\",\n      \"method\": \"NMR structure of RNA stem-loops, RNA-protein binding assays, competitive binding studies, splicing reporter assays, U2AF2 recruitment analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure of regulatory RNA elements plus biochemical competitive binding and functional splicing assays\",\n      \"pmids\": [\"35921415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MALT1 is required for EGFR-induced NF-κB activation in cancer cells, functioning mainly as a scaffold protein by recruiting TRAF6 to the IKK complex. MALT1 deficiency abolished both NF-κB and STAT3 activation in EGFR-driven lung tumors in vivo, attributed to defective IL-6 production.\",\n      \"method\": \"MALT1 knockdown in cancer cells, triple-transgenic EGFR-driven lung cancer mouse model (Malt1-/-), NF-κB/STAT3 activation assays, IL-6 production measurement, tumor burden analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with mechanistic pathway analysis\",\n      \"pmids\": [\"25982276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Gab2 facilitates assembly of the CARMA3-BCL10-MALT1 signalosome in endothelial cells. MALT1 within this complex mediates IL-1β-induced Rho-dependent exocytosis of P-selectin and von Willebrand factor, NF-κB-dependent tissue factor expression, and neutrophil adhesion. MALT1 inhibition or Gab2 silencing suppresses venous thrombosis in mice.\",\n      \"method\": \"Gene silencing (Gab2, MALT1), MALT1 pharmacological inhibition (mepazine), P-selectin/VWF exocytosis assays, Rho activity assays, inferior vena cava ligation DVT mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic and pharmacological evidence in vitro and in vivo, single lab\",\n      \"pmids\": [\"35895897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAF6 recruits to MALT1 in activated T cells and is indispensable for NF-κB signaling, but also counteracts basal MALT1 protease activity in resting T cells via a homeostatic suppression mechanism. Loss of this suppression leads to fatal autoimmune inflammation fully reversed by MALT1 protease inactivation.\",\n      \"method\": \"T cell-conditional TRAF6 knockout mice, MALT1 protease activity measurement in resting vs. activated T cells, MALT1 protease-dead genetic rescue, pharmacological MALT1 inhibitor treatment\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional genetic models with biochemical MALT1 activity assays and full phenotypic rescue\",\n      \"pmids\": [\"34767456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Keratinocyte-intrinsic BCL10/MALT1 signaling amplifies responses to IL-17A, IL-1β, and TNF and is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation. Selective keratinocyte BCL10/MALT1 deletion completely rescues Card14 gain-of-function-driven skin pathology.\",\n      \"method\": \"Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function mouse model, artificial BCL10/MALT1 activating engager molecule, cytokine response assays, skin inflammation scoring\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic models with gain-of-function and loss-of-function validation\",\n      \"pmids\": [\"34826258\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MALT1 is a paracaspase that functions as both a scaffolding protein and an arginine-specific protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome: upon antigen receptor or GPCR stimulation, MALT1 is polyubiquitinated (K63-linked, by TRAF6) and dimerizes, enabling it to recruit NEMO/IKKγ for canonical NF-κB activation, while its protease activity cleaves and inactivates negative regulators of NF-κB (A20, CYLD, RelB, HOIL1) and other substrates (N4BP1, c-Jun), thereby amplifying and sustaining inflammatory gene expression; MALT1 protease activity is additionally regulated by CK1α-mediated phosphorylation, TRAF6-mediated homeostatic suppression in resting T cells, and alternative splicing that controls TRAF6 recruitment, and its constitutive activation in ABC-DLBCL and other malignancies drives lymphoma survival and proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MALT1 is a paracaspase that functions as both a scaffold and an arginine-specific cysteine protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome, serving as a central integrator of NF-κB activation downstream of antigen receptors, GPCRs, and innate immune receptors in lymphocytes, keratinocytes, and other cell types [PMID:17948050, PMID:17101977, PMID:27113748]. As a scaffold, MALT1 undergoes TRAF6-mediated K63-linked polyubiquitination that recruits NEMO/IKKγ for IKK activation, and BCL10 filament-templated MALT1 dimerization cooperatively assembles higher-order signalosomes with TRAF6 for switch-like NF-κB responses; alternative splicing (MALT1A/B) and CK1α-mediated phosphorylation further tune scaffold output [PMID:17948050, PMID:29382759, PMID:27068814, PMID:31644910]. Dimerization-dependent protease activity cleaves and inactivates negative regulators of NF-κB—including A20, CYLD, RelB, and HOIL1—after arginine residues, amplifying canonical NF-κB and JNK signaling, while TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells to prevent autoimmunity [PMID:18223652, PMID:21448133, PMID:21873235, PMID:27006117, PMID:34767456]. MALT1 protease activity is required for regulatory T cell suppressive function, Th17 differentiation, marginal zone B cell development, and contributes to oncogenic NF-κB in ABC-DLBCL; in keratinocytes, CBM signaling downstream of psoriasis-associated CARD14 mutations drives psoriasiform inflammation [PMID:31138793, PMID:25665967, PMID:34826258].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Early characterization established that MALT1 is a cytoplasmic protein subject to rapid proteasomal turnover, whereas the oncogenic API2-MALT1 fusion escapes degradation—raising the question of how MALT1 stability is regulated and how the fusion contributes to lymphomagenesis.\",\n      \"evidence\": \"Subcellular fractionation, proteasome inhibitor treatment, and Western blot stability assays in overexpression systems\",\n      \"pmids\": [\"14603249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no endogenous protein analysis\", \"Mechanism of proteasomal targeting not identified\", \"No functional consequence of stabilization tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of nuclear export signals in MALT1 revealed that it undergoes constitutive nucleocytoplasmic shuttling and actively maintains BCL10 in the cytoplasm, establishing that MALT1 has a localization-regulatory role beyond signal transduction.\",\n      \"evidence\": \"Deletion mutants, leptomycin B (NES inhibitor) treatment, and cellular fractionation\",\n      \"pmids\": [\"16123224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab observation\", \"Functional significance of nuclear shuttling for NF-κB signaling not resolved\", \"Endogenous protein shuttling not tracked\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The CBM complex was shown to operate beyond lymphocytes: BCL10 and MALT1 are essential and selective mediators of GPCR-induced NF-κB activation in non-immune cells (fibroblasts, hepatocytes), establishing MALT1 as a broadly utilized NF-κB signaling node.\",\n      \"evidence\": \"Bcl10−/− and Malt1−/− MEFs and dominant-negative mutants with NF-κB pathway-selective readouts for LPA and angiotensin II stimulation\",\n      \"pmids\": [\"17101977\", \"17095601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream mechanism linking GPCRs to CBM assembly not defined\", \"Whether MALT1 protease activity is engaged downstream of GPCRs was untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The molecular mechanism linking MALT1 to IKK was resolved: TRAF6-mediated K63-linked polyubiquitination of MALT1 C-terminal lysines creates a docking platform for NEMO/IKKγ, directly connecting CBM assembly to IKK activation.\",\n      \"evidence\": \"In vitro ubiquitination with recombinant TRAF6, Malt1−/− T cell reconstitution with lysine mutants, IL-2 production\",\n      \"pmids\": [\"17948050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of NEMO recruitment not determined\", \"Whether other E3 ligases contribute was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In B cells, MALT1 was found to selectively activate c-Rel without being required for IKK activation or RelA induction, revealing that MALT1 controls a specific NF-κB transcriptional subprogram rather than acting as a generic IKK activator.\",\n      \"evidence\": \"Malt1−/− B cells with NF-κB subunit-specific DNA-binding and survival assays\",\n      \"pmids\": [\"17660823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of c-Rel selectivity not determined\", \"Whether this selectivity extends to T cells was untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"MALT1 was identified as an active protease (paracaspase) that cleaves A20 after Arg-439, removing a key NF-κB negative regulator and establishing the paradigm of MALT1 protease-mediated amplification of NF-κB signaling.\",\n      \"evidence\": \"In vitro cleavage assay, R439 mutagenesis, co-IP of A20 into BCL10-MALT1 complex, NF-κB reporter assays\",\n      \"pmids\": [\"18223652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire unknown\", \"Whether protease activity is essential in vivo was untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A reciprocal regulatory circuit was established: A20 deubiquitinates K63-linked chains on MALT1 to limit IKK recruitment, while MALT1 protease cleaves A20, creating a feedback loop that controls NF-κB signaling duration.\",\n      \"evidence\": \"Malt1−/− T cell reconstitution, ubiquitin chain analysis, IKK activity assays\",\n      \"pmids\": [\"19494296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal dynamics of this feedback in vivo not resolved\", \"Whether other DUBs target MALT1 was unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"MALT1 was shown to participate in non-canonical NF-κB signaling: it is required for BAFF-induced p100 processing and RelB nuclear translocation in marginal zone B cells, interacting with TRAF3 to modulate its levels.\",\n      \"evidence\": \"Malt1−/− B cells, MALT1-TRAF3 co-IP, NF-κB2 processing assays, BAFF-overexpression in vivo model\",\n      \"pmids\": [\"19917778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MALT1 protease activity is required for non-canonical signaling was unclear\", \"Mechanism of TRAF3 level regulation by MALT1 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The substrate repertoire of MALT1 protease expanded to include CYLD (enabling JNK activation) and RelB (enabling canonical NF-κB DNA binding by removing an inhibitory competitor), demonstrating that MALT1 cleavage of multiple negative regulators coordinates NF-κB and JNK pathway activation.\",\n      \"evidence\": \"In vitro cleavage assays with mutagenesis, Malt1−/− reconstitution, JNK assays, NF-κB DNA-binding assays, DLBCL survival assays\",\n      \"pmids\": [\"21448133\", \"21873235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each substrate cleavage to NF-κB output not quantified\", \"In vivo physiological significance of individual cleavage events untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structural and biochemical studies established that MALT1 protease activity depends on dimerization (not autocleavage), with arginine-directed specificity and kinetics comparable to caspases, and that the C-terminal Ig-like domain is essential for activity.\",\n      \"evidence\": \"Crystal structure, dimer interface mutagenesis, positional-scanning substrate libraries, kinetic measurements of CYLD cleavage\",\n      \"pmids\": [\"22366302\", \"22309193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length MALT1 structure with BCL10 not available\", \"Mechanism of activation at the CBM level not structurally resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"MALT1 auto-proteolysis after Arg-149 was identified as a post-activation event that does not regulate catalytic activity per se but is required for optimal NF-κB-dependent transcription, and p62 was found to scaffold the BCL10-MALT1-IKK signalosome in the cytosol.\",\n      \"evidence\": \"R149A mutagenesis with transcriptome analysis in Jurkat T cells; p62−/− T cells with confocal imaging of signalosome assembly\",\n      \"pmids\": [\"25105596\", \"24825920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How autocleavage enhances transcription mechanistically is unknown\", \"Whether p62 scaffolding is cell-type specific was untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MALT1 protease-dead knock-in mice revealed that protease activity is essential in vivo for marginal zone/B1 B cell development, T cell proliferation, dendritic cell innate responses, and immune homeostasis, while its scaffolding function alone is insufficient.\",\n      \"evidence\": \"MALT1 protease-dead knock-in mouse with comprehensive flow cytometry, proliferation assays, immunization, and dendritic cell cytokine assays\",\n      \"pmids\": [\"25665967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of individual substrate cleavages to each phenotype not dissected\", \"Whether protease-dead mice develop lymphoma or autoimmunity long-term was not fully characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MALT1 was established as a key effector of EGFR-driven oncogenic signaling: it scaffolds TRAF6 recruitment to IKK for NF-κB/STAT3 activation and IL-6 production in EGFR-driven lung tumors, demonstrating CBM pathway cooption by receptor tyrosine kinases in cancer.\",\n      \"evidence\": \"MALT1 knockdown in cancer cells, Malt1−/− triple-transgenic EGFR-driven lung cancer mouse model, tumor burden analysis\",\n      \"pmids\": [\"25982276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MALT1 protease vs. scaffold function drives lung tumorigenesis not separated\", \"Applicability to other RTK-driven cancers untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Alternative splicing was shown to control MALT1 scaffolding: the MALT1A isoform (exon7-included) facilitates TRAF6 recruitment without altering protease activity, and TCR stimulation induces exon7 inclusion via hnRNP U regulation, adding a splicing-based regulatory layer to CBM signaling.\",\n      \"evidence\": \"Isoform-selective knockdown, TRAF6 co-IP, hnRNP U knockdown, splicing reporters, T cell activation assays\",\n      \"pmids\": [\"27068814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MALT1A/B ratio is dysregulated in disease was not determined\", \"How TCR stimulation modulates hnRNP U activity was unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"MALT1 substrate repertoire expanded further: HOIL1 (LUBAC subunit) cleavage removes linear ubiquitin chain-generating capacity to amplify NF-κB, and CARD14 was identified as a MALT1 activator in keratinocytes with psoriasis-associated gain-of-function mutations constitutively driving MALT1 protease activity.\",\n      \"evidence\": \"In vitro cleavage assays, cleavage-resistant HOIL1 rescue, CARD14-MALT1 co-IP and protease activity in primary keratinocytes\",\n      \"pmids\": [\"27006117\", \"27113748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOIL1 cleavage contributes to ABC-DLBCL pathogenesis in patients was untested\", \"Full spectrum of CARD14-MALT1 substrates in keratinocytes unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM revealed the structural basis for CBM signalosome assembly: CARMA1-nucleated BCL10 CARD filaments serve as a template for cooperative MALT1 dimerization and subsequent TRAF6 decoration, explaining the switch-like, all-or-none NF-κB activation behavior.\",\n      \"evidence\": \"4.0-Å cryo-EM of BCL10 filament, negative-stain EM of CBM-TRAF6, time-lapse confocal imaging\",\n      \"pmids\": [\"29382759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of MALT1 on the filament not achieved\", \"How filament disassembly/termination occurs is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple regulatory inputs and functional outputs of MALT1 were defined: CK1α phosphorylates MALT1 C-terminal serines to enhance NF-κB signaling; HECTD3-mediated K27/K29-linked ubiquitination at K648 promotes NF-κB and Th17 differentiation; MALT1 cleaves N4BP1 to relieve HIV-1 latency; and MALT1 protease activity is essential for Treg suppressive function and tumor immune evasion.\",\n      \"evidence\": \"Mass spectrometry phosphoproteomics with CK1α kinase assays; Hectd3−/− mice with linkage-specific ubiquitination; N4BP1 cleavage assay with HIV-1 reactivation; conditional BCL10 knockout and MALT1 protease-dead mice in melanoma models\",\n      \"pmids\": [\"31644910\", \"30741923\", \"31133753\", \"31138793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of phosphorylation and ubiquitination signals on MALT1 not resolved\", \"Whether N4BP1 cleavage is relevant beyond HIV latency reversal unknown\", \"Therapeutic window for MALT1 inhibition in cancer immunotherapy not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural pharmacology of MALT1 was advanced: an allosteric inhibitor locks the protease inactive by displacing Trp580, and this same mechanism rescues the destabilizing W580S patient mutation, demonstrating that allosteric regulation couples protease domain conformation to Ig-like domain interactions.\",\n      \"evidence\": \"Structural analysis of inhibitor binding, protein stability assays, patient lymphocyte NF-κB/JNK signaling recovery\",\n      \"pmids\": [\"30692685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether allosteric inhibitors are effective in vivo in disease models not shown in this study\", \"Full landscape of loss-of-function MALT1 mutations in immunodeficiency not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"MALT1 protease was linked to metabolic reprogramming in Th17 cells: it stabilizes c-Jun by cleavage, promoting GLS1 expression and glutaminolysis that drives H3 acetylation at the Il17a promoter and Th17/γδT17 differentiation in psoriasis.\",\n      \"evidence\": \"MALT1 inhibitor, c-Jun cleavage assay, ChIP for H3 acetylation, GLS1 analysis, mouse psoriasis models\",\n      \"pmids\": [\"32831293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Whether metabolic reprogramming by MALT1 extends beyond Th17 cells untested\", \"Direct protease cleavage site on c-Jun not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TRAF6 was revealed to have a dual role: beyond activating NF-κB through MALT1 ubiquitination, TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells, and loss of this suppression causes fatal autoimmunity fully rescued by MALT1 protease inactivation.\",\n      \"evidence\": \"T cell-conditional TRAF6 knockout mice, MALT1 protease measurement in resting vs. activated cells, genetic protease-dead rescue, pharmacological MALT1 inhibitor\",\n      \"pmids\": [\"34767456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of TRAF6-mediated protease suppression not defined\", \"Whether other ubiquitin ligases contribute to basal MALT1 suppression unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Keratinocyte-intrinsic BCL10/MALT1 signaling was established as a driver of psoriasiform inflammation: it amplifies IL-17A/IL-1β/TNF responses and is necessary and sufficient for CARD14 gain-of-function-driven skin disease.\",\n      \"evidence\": \"Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function model, artificial CBM activating molecules\",\n      \"pmids\": [\"34826258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MALT1 protease vs. scaffold function drives skin inflammation not separated\", \"Therapeutic efficacy of MALT1 inhibitors in psoriasis patients unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The RNA structural basis of MALT1 alternative splicing was resolved: hnRNP U and hnRNP L competitively bind stem-loop structures flanking exon7, with hnRNP L disrupting these elements to recruit U2AF2 and promote MALT1A expression.\",\n      \"evidence\": \"NMR structure of regulatory RNA stem-loops, competitive RNA-protein binding assays, splicing reporter assays\",\n      \"pmids\": [\"35921415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TCR activation shifts the hnRNP U/L balance mechanistically remains unknown\", \"Whether splicing dysregulation contributes to MALT1-dependent malignancies untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MALT1 function was extended to endothelial cells: Gab2 facilitates CARMA3-BCL10-MALT1 assembly to mediate IL-1β-induced Rho-dependent exocytosis and NF-κB-driven tissue factor expression, contributing to venous thrombosis.\",\n      \"evidence\": \"Gab2/MALT1 silencing, pharmacological MALT1 inhibition, P-selectin/VWF exocytosis, IVC ligation DVT mouse model\",\n      \"pmids\": [\"35895897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding\", \"Whether MALT1 protease or scaffold function mediates thrombotic phenotype not resolved\", \"Relevance to human venous thromboembolism unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full atomic structure of MALT1 within the assembled CBM filament, the molecular mechanism by which TRAF6 suppresses basal MALT1 protease activity, the complete inventory of MALT1 substrates across cell types, and whether selective MALT1 protease inhibitors can be therapeutically deployed in autoimmunity and cancer without unacceptable immunosuppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length MALT1-on-filament atomic structure\", \"TRAF6 suppression mechanism molecularly undefined\", \"Therapeutic index of MALT1 inhibition in patients unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 6, 7, 13, 15, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9, 12, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 9, 10, 11, 25, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11, 14, 21, 22, 31, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 15, 25, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 24, 25]}\n    ],\n    \"complexes\": [\n      \"CBM signalosome (CARMA/CARD-BCL10-MALT1)\",\n      \"BCL10-MALT1 complex\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"TRAF6\",\n      \"CARD11\",\n      \"CARD14\",\n      \"CARD10\",\n      \"NEMO\",\n      \"TRAF3\",\n      \"SQSTM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}