{"gene":"MALT1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2008,"finding":"TCR stimulation induces recruitment of A20 into a complex with MALT1 and BCL10, leading to MALT1-mediated proteolytic cleavage of A20 after arginine 439, impairing its NF-κB-inhibitory function. API2-MALT1 fusion also cleaves A20. This identifies A20 as a direct substrate of MALT1 paracaspase activity.","method":"Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis of cleavage site, T cell stimulation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro cleavage assay with mutagenesis of cleavage site, replicated in multiple cell contexts including T cells and API2-MALT1-expressing cells","pmids":["18223652"],"is_preprint":false},{"year":2003,"finding":"Malt1 is essential for TCR-induced T cell activation, proliferation, and IL-2 production. Malt1 operates downstream of Bcl10 and controls the catalytic activity of the canonical IKK complex, as well as JNK and p38 MAP kinase signaling. Malt1 is dispensable for TNF-α or IL-1 signaling, establishing signal-specific pathway position.","method":"Malt1 knockout mouse model, genetic epistasis (Bcl10 vs Malt1 deficiency), T cell activation assays, IKK activity assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts and epistasis analysis, replicated by multiple subsequent studies","pmids":["14614861"],"is_preprint":false},{"year":2007,"finding":"MALT1 is polyubiquitinated upon T cell activation. TRAF6 associates with MALT1 after T cell activation and mediates K63-linked polyubiquitination of MALT1 in vitro and in vivo. Ubiquitin chains on MALT1 recruit the IKK regulatory subunit NEMO/IKKγ, directing TCR signals to the canonical NF-κB pathway. Multiple C-terminal lysine residues serve as ubiquitin acceptor sites.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis of lysine acceptor sites, rescue experiments in Malt1-/- T cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution, mutagenesis of acceptor sites, functional rescue in knockout T cells","pmids":["17948050"],"is_preprint":false},{"year":2007,"finding":"MALT1 selectively activates c-Rel (but not RelA) downstream of B cell receptor signaling. BCL10 is required for IKK recruitment into lipid rafts and activation of both RelA and c-Rel, whereas MALT1 is dispensable for IKK recruitment and RelA induction but specifically controls a c-Rel subprogram governing survival signaling.","method":"Malt1 knockout mouse B cells, BCR stimulation, IKK fractionation into lipid rafts, NF-κB subunit analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal assays distinguishing MALT1 vs BCL10 functions","pmids":["17660823"],"is_preprint":false},{"year":2009,"finding":"A20 deubiquitinates MALT1 by removing K63-linked ubiquitin chains, preventing sustained MALT1-IKK interaction and serving as a negative regulator of IKK activity. Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but is dispensable for initial IKK/NF-κB signaling in CD4+ T cells.","method":"Antagonistic peptide inhibition, reconstitution in Malt1-/- T cells, TCR/CD28 co-stimulation assays, proteasome inhibition experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary methods (peptide inhibitor, genetic reconstitution) with clear separation of scaffold vs protease functions","pmids":["19494296"],"is_preprint":false},{"year":2011,"finding":"Malt1 proteolytically cleaves and inactivates CYLD (a deubiquitinase), which is specifically required for TCR-induced JNK activation and expression of a subset of genes. CYLD cleavage by MALT1 also occurs upon overexpression of oncogenic API2-MALT1.","method":"T cell stimulation assays, identification of CYLD as MALT1 substrate, API2-MALT1 overexpression, gene expression profiling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate identification with functional consequence (JNK activation), replicated in oncogenic fusion context","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 controlling DNA binding of RelA- and c-Rel-containing NF-κB complexes to promote canonical NF-κB activation in lymphocytes and lymphoma cells.","method":"In vitro cleavage assay, site-directed mutagenesis of cleavage site, RelB overexpression, NF-κB reporter and target gene analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage with defined cleavage site, functional rescue experiments, single lab with multiple orthogonal methods","pmids":["21873235"],"is_preprint":false},{"year":2012,"finding":"MALT1 paracaspase is activated by dimerization without cleavage (analogous to apical caspases). The catalytic domain alone recapitulates full-length MALT1 substrate specificity: strict requirement for Arg at P1 position, with peptide length constraints. Optimal peptidyl substrate cleavage rates (kcat/Km ~10³–10⁴ M⁻¹·s⁻¹) are comparable to caspase-8.","method":"Recombinant protein expression/purification, positional-scanning peptidyl substrate libraries, kinetic analysis, in vitro cleavage of CYLD","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro biochemical reconstitution with substrate library screening and kinetic measurements, single lab but multiple orthogonal methods","pmids":["22309193"],"is_preprint":false},{"year":2012,"finding":"The MALT1 inhibitor MI-2 directly binds MALT1 and irreversibly inhibits its protease function, suppressing ABC-DLBCL cell growth in vitro and in vivo, demonstrating that MALT1 proteolytic activity is essential for ABC-DLBCL cell survival.","method":"MALT1 activity assay, direct binding assay, NF-κB reporter, xenotransplant mouse model, cell viability assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, in vitro and in vivo activity, pharmacological validation of protease function","pmids":["23238016"],"is_preprint":false},{"year":2014,"finding":"Targeted inactivation of Malt1 paracaspase (protease-dead knock-in mice) causes a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration. Paracaspase activity is essential for Treg and innate-like B cell development. Malt1 cleaves mRNA stability regulators Roquin-1, Roquin-2, and Regnase-1 in addition to NF-κB inhibitors, controlling IFNγ production by effector lymphocytes.","method":"Malt1 protease-dead knock-in mouse model, substrate identification (Roquin-1/2, Regnase-1 cleavage), adoptive transfer, in vivo phenotypic analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knock-in model with multiple orthogonal readouts and identification of novel substrate class (mRNA stability regulators)","pmids":["25456129"],"is_preprint":false},{"year":2014,"finding":"MALT1 undergoes auto-proteolytic cleavage after Arg-149 (between the death domain and first Ig-like domain) during antigen receptor signaling. This auto-cleavage does not affect proteolytic activity but is required for optimal NF-κB target gene expression (IL-2, CSF2) downstream of nuclear NF-κB accumulation.","method":"Site-directed mutagenesis (R149A), transcriptome analysis, IκBα phosphorylation assay, NF-κB reporter, rescue in Jurkat T cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of cleavage site with transcriptome-wide functional validation, single lab multiple orthogonal methods","pmids":["25105596"],"is_preprint":false},{"year":2015,"finding":"MALT1 cleaves the LUBAC subunit HOIL-1 in activated T cells. Cleavage generates a C-terminal fragment with LUBAC inhibitory properties, providing gain-of-function negative feedback regulation of NF-κB signaling, while the N-terminal fragment retains HOIP-dependent NF-κB support activity.","method":"T cell activation assays, API2-MALT1 overexpression, cleavage product characterization, LUBAC functional assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification with functional characterization of cleavage fragments, single lab","pmids":["26573773"],"is_preprint":false},{"year":2016,"finding":"Alternative splicing of MALT1 produces two conserved isoforms (MALT1A containing exon7, MALT1B without). Exon7 inclusion in MALT1A facilitates TRAF6 recruitment, augmenting MALT1 scaffolding function but not protease activity. hnRNP U suppresses exon7 inclusion; naive CD4+ T cells express predominantly MALT1B, and TCR stimulation induces MALT1A expression.","method":"Selective isoform depletion, TRAF6 co-immunoprecipitation, T cell signaling assays, hnRNP U knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for TRAF6, selective isoform knockdown with defined signaling readout, multiple orthogonal methods single lab","pmids":["27068814"],"is_preprint":false},{"year":2016,"finding":"CARD14 physically interacts with MALT1 and activates MALT1 proteolytic activity in keratinocytes. Psoriasis-associated CARD14 mutations enhance MALT1 protease activation and NF-κB, p38 and JNK signaling. MALT1 deficiency or pharmacological inhibition blocks CARD14 mutant-induced cytokine/chemokine expression in primary keratinocytes.","method":"Co-immunoprecipitation, MALT1 protease activity assay, siRNA knockdown, pharmacological inhibition in primary human keratinocytes","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct physical interaction and protease activity demonstrated, multiple complementary approaches in primary human cells","pmids":["27113748"],"is_preprint":false},{"year":2016,"finding":"Psoriasis gain-of-function CARD14 mutants constitutively interact with BCL10 and MALT1, trigger BCL10- and MALT1-dependent NF-κB activation in keratinocytes by disrupting the CARD14 linker region autoinhibition. CARD14(E138A) also stimulates MALT1 paracaspase activity and activates ERK1/2 and p38α MAP kinases.","method":"Co-immunoprecipitation, NF-κB reporter assays, MALT1 protease activity assay, MAP kinase phosphorylation assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary assays in a single lab, mechanistic dissection of autoinhibition relief","pmids":["27071417"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of BCL10 CARD filament at 4.0 Å resolution redefines CARD-CARD interactions. MALT1 cooperatively interacts with BCL10 filaments and immediately dimerizes within the BCL10 filamentous scaffold. TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, producing all-or-none IKK/NF-κB activation.","method":"Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, in vitro reconstitution of CBM-TRAF6 filaments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus functional reconstitution and live imaging, single lab with multiple orthogonal methods","pmids":["29382759"],"is_preprint":false},{"year":2019,"finding":"MALT1 cleaves N4BP1 at Arg-509 upon CD4+ T cell activation, inactivating N4BP1's antiviral RNase activity. MALT1-mediated N4BP1 cleavage facilitates reactivation of latent HIV-1 proviruses in T cells.","method":"MALT1 cleavage assay, mutational analysis, MALT1 knockout studies, HIV-1 latency reactivation assays","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate cleavage site identified by mutagenesis, confirmed by knockout, functional consequence in viral reactivation demonstrated","pmids":["31133753"],"is_preprint":false},{"year":2019,"finding":"An allosteric MALT1 inhibitor binds by displacing the Trp580 side chain, locking MALT1 in an inactive conformation. A patient homozygous for MALT1 W580S mutation suffered combined immunodeficiency due to protein instability; allosteric inhibitors stabilize MALT1-W580S, restoring NF-κB and JNK signaling in patient lymphocytes (molecular corrector mechanism).","method":"X-ray crystallography (inhibitor binding mode), thermal stability assays, patient lymphocyte signaling rescue, compound washout/substrate cleavage recovery","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination of inhibitor binding site, functional rescue in patient-derived cells, mechanistic insight into Trp580 role in domain stability","pmids":["30692685"],"is_preprint":false},{"year":2019,"finding":"MALT1 phosphorylation at multiple serine residues in the C-terminus occurs transiently upon TCR/CD28 co-stimulation via CK1α, which also mediates CBM signalosome assembly. MALT1 phosphorylation fosters canonical NF-κB signaling and promotes survival of ABC-DLBCL cells.","method":"Unbiased mass spectrometry phosphoproteomics, phospho-specific antibodies, CK1α kinase assays, Jurkat and primary murine CD4 T cell signaling assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification plus phospho-specific antibody validation plus kinase assignment, multiple cell contexts","pmids":["31644910"],"is_preprint":false},{"year":2021,"finding":"TRAF6 has a dual role: it is indispensable for MALT1 scaffolding-dependent NF-κB signaling in activated T cells, but also counteracts basal MALT1 protease activity in resting T cells. Loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is fully rescued by genetic or pharmacological MALT1 protease inactivation.","method":"Genetically engineered mouse models (T cell-specific TRAF6 deletion), biochemical analyses of MALT1-TRAF6 interaction, pharmacological MALT1 inhibition rescue","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models combined with pharmacological rescue and biochemical interaction studies, bidirectional regulation demonstrated","pmids":["34767456"],"is_preprint":false},{"year":2005,"finding":"MALT1 contains nuclear export signals (NES) in its C-terminal region and shuttles between the nucleus and cytoplasm in an NES-dependent manner. MALT1 also controls the cytoplasmic localization of BCL10 by promoting its nuclear export.","method":"Deletion mutant analysis, leptomycin B treatment (NES inhibitor), subcellular localization by fluorescence microscopy","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mutant analysis and pharmacological NES blockade, localization without full mechanistic pathway connection, single lab","pmids":["16123224"],"is_preprint":false},{"year":2008,"finding":"The interaction between BCL10 and MALT1 involves multiple protein domains: the MALT1 death domain and the BCL10 CARD both contribute to the interaction in addition to the previously known Ig-like domain/BCL10 post-CARD region interaction. Residues Asp80 and Glu84 in helix 5 of the BCL10 CARD directly contact MALT1.","method":"FRET analysis in T cells, co-immunoprecipitation, point mutagenesis of BCL10 CARD, molecular modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP plus mutagenesis in single lab, multiple orthogonal approaches","pmids":["18806265"],"is_preprint":false},{"year":2006,"finding":"Bcl10 and Malt1 are required for LPA (lysophosphatidic acid)-induced NF-κB activation downstream of G protein-coupled receptors in non-immune cells (murine embryonic fibroblasts). They cooperate with PKCs selectively for LPA-induced NF-κB but are dispensable for JNK, p38, ERK, and Akt signaling in this context.","method":"Bcl10- or Malt1-deficient murine embryonic fibroblasts, LPA stimulation, IκBα degradation assay, MAP kinase and Akt assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout model with signaling pathway specificity established by multiple orthogonal assays","pmids":["17095601"],"is_preprint":false},{"year":2016,"finding":"LUBAC subunit HOIL1 is cleaved by MALT1 following antigen receptor engagement in lymphocytes and is constitutively processed in ABC-DLBCL cells. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, identifying HOIL1 as a negative regulator cleaved by MALT1.","method":"T cell receptor stimulation assays, MALT1-resistant mutant overexpression, NF-κB reporter, cytokine measurement","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification with functional validation using cleavage-resistant mutant, single lab","pmids":["27006117"],"is_preprint":false},{"year":2014,"finding":"A TCR-dependent cytosolic p62-Bcl10-Malt1-IKK signalosome forms in effector T cells. p62-dependent clustering of signaling components stimulates IKK activation and NF-κB translocation. Inhibiting TAK1 or IKK blocks IKK phosphorylation but not p62-Bcl10-Malt1 cluster formation, placing IKK activation after signalosome assembly.","method":"Genetic epistasis (p62 knockout T cells), fluorescence microscopy of signalosome clusters, kinase inhibitor treatment, IκBα phosphorylation assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus live imaging plus kinase inhibitor epistasis, single lab","pmids":["24825920"],"is_preprint":false},{"year":2010,"finding":"BCL10, MALT1 and IKK inducibly associate with IκBα in a complex distinct from the early CK1α-CBM signalosome during TCR signaling. IκBα knockdown alters BCL10-MALT1 ubiquitylation and impairs MALT1 reorganization into large cytoplasmic structures, suggesting IκBα participates in MALT1 recycling after activation.","method":"Co-immunoprecipitation, siRNA knockdown of signalosome components, fluorescence microscopy of MALT1 structures","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and siRNA knockdown, localization studies, single lab with several complementary approaches","pmids":["20551178"],"is_preprint":false},{"year":2015,"finding":"MALT1 is an intrinsic regulator of regulatory T cell (Treg) development: Malt1-/- mice have a reduced number of Tregs, with nTregs essentially absent in young mice. iTregs from Malt1-/- mice have higher TLR2 expression and enhanced induction by TLR2 ligands, indicating MALT1 suppresses peripheral iTreg induction during inflammation.","method":"Malt1 knockout mouse model, T cell adoptive transfer, in vitro Treg suppression assays, TLR2 ligand stimulation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with multiple immunological readouts, single lab","pmids":["26405015"],"is_preprint":false},{"year":2022,"finding":"Alternative splicing of MALT1 exon7 is controlled by competitive binding of hnRNP U and hnRNP L to RNA stem-loop structures flanking exon7. hnRNP U stabilizes stem-loop conformations maintaining exon7 skipping (MALT1B); hnRNP L disrupts these structures to facilitate U2AF2 recruitment and exon7 inclusion (MALT1A).","method":"NMR structural analysis of RNA stem-loops, RNA binding protein interaction studies, splicing reporter assays, RBP knockdown","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural NMR plus functional splicing assays, mechanism of splice site regulation defined at molecular level, single lab with multiple orthogonal methods","pmids":["35921415"],"is_preprint":false},{"year":2019,"finding":"MALT1 protease activity has a T cell-intrinsic role in suppressing autoimmunity. T cell-conditional protease-dead knock-in mice (Malt1-PDT) phenocopy full-body protease-dead mice, developing ataxia and multi-organ inflammation. Reconstitution of full-body Malt1-PD mice with T cell-specific wild-type human MALT1 eliminates all signs of autoimmunity.","method":"T cell-conditional Malt1 protease-dead knock-in mice, bone marrow reconstitution, T cell-specific rescue with human MALT1","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic models with rescue experiment, clear T cell-intrinsic function established","pmids":["31474984"],"is_preprint":false},{"year":2016,"finding":"MALT1 controls an MYC-driven gene expression network in mantle cell lymphoma predominantly by increasing MYC protein stability, representing a regulatory mechanism linking BCR/MALT1 signaling to MYC in both MCL and primary mouse splenocytes.","method":"MALT1 RNA interference and pharmacological inhibition, gene expression profiling, MYC protein stability assay, primary mouse splenocyte analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with gene expression profiling, mechanism confirmed in primary cells, single lab","pmids":["27864294"],"is_preprint":false},{"year":2015,"finding":"MALT1 paracaspase catalytic activity requires activation by monoubiquitination-induced dimerization. Constitutive MALT1 activity in specific B cell lymphoma subsets results from chromosomal translocations or upstream regulatory mutations.","method":"Review/summary but grounded in biochemical studies of dimerization and ubiquitination-dependent activation","journal":"Current opinion in chemical biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper summarizing prior findings, no new primary experimental data","pmids":["25285878"],"is_preprint":false},{"year":2013,"finding":"API2-MALT1 fusion promotes NF-κB activation by binding RIP1 and inducing its ubiquitination at Lys-377. TRAF2 recruitment to the API2 moiety is required for RIP1 ubiquitination and NF-κB activation. This ubiquitination requires the concerted actions of both API2 and MALT1 moieties (gain of function).","method":"Co-immunoprecipitation identifying RIP1 as API2-MALT1 binding partner, ubiquitination assays, TRAF2 knockdown, NF-κB reporter","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay plus knockdown, single lab","pmids":["23770847"],"is_preprint":false},{"year":2020,"finding":"MALT1 protease stabilizes c-Jun by preventing its degradation, supporting GLS1 (glutaminase 1) expression in psoriatic T cells. c-Jun directly binds the GLS1 promoter region, linking MALT1 protease activity to glutaminolysis and Th17 differentiation.","method":"MALT1 inhibition in psoriatic CD4+ and γδ T cells, c-Jun stability assay, ChIP assay for c-Jun on GLS1 promoter, metabolic assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus ChIP plus metabolic assays, single lab, mechanistic chain established","pmids":["32831293"],"is_preprint":false},{"year":2019,"finding":"MALT1 knockdown or pharmacological inhibition in glioblastoma stem-like cells increases endo-lysosome abundance, impairs autophagic flux, and causes lysosomal-mediated cell death concomitant with mTOR inactivation and dispersal from endo-lysosomes, identifying a role for MALT1 in endo-lysosome homeostasis.","method":"MALT1 knockdown, pharmacological inhibitors in vitro and in vivo, lysosome abundance quantification, autophagic flux assays, mTOR localization imaging","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition with multiple orthogonal readouts, single lab","pmids":["31774199"],"is_preprint":false},{"year":2023,"finding":"MALT1-mediated CYLD cleavage promotes NF-κB signaling and proliferation in BCR-dependent lymphomas. Overexpression of WT CYLD or MALT1-cleavage-resistant CYLD mutant reduces IκBα phosphorylation, represses NF-κB target genes, and impairs lymphoma cell growth. CYLD silencing reduces sensitivity to BTK inhibitor ibrutinib.","method":"MALT1 protease assay, MALT1-cleavage-resistant CYLD mutant overexpression, IκBα phosphorylation assay, NF-κB reporter, ibrutinib sensitivity assay","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage-resistant mutant provides clean mechanistic validation, multiple signaling readouts, single lab","pmids":["36922488"],"is_preprint":false},{"year":2022,"finding":"HECTD4 E3 ubiquitin ligase mediates MALT1 ubiquitination and degradation. Knockdown of HECTD4 reduces MALT1 ubiquitination, increases MALT1 stability, and promotes GluN2B phosphorylation and calcium overload in neurons via MALT1-dependent STEP61 degradation. MALT1 siRNA counteracts HECTD4 knockdown-induced injury.","method":"Co-IP (HECTD4-GluN2B interaction), ubiquitination assays, siRNA knockdown, calcium imaging, ischemic stroke rat model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with genetic rescue, in vivo model, single lab","pmids":["36527595"],"is_preprint":false}],"current_model":"MALT1 (PCASP1/MLT) is a paracaspase that functions as both a scaffold protein and an Arg-specific protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome: upon antigen receptor or GPCR stimulation, MALT1 is K63-polyubiquitinated by TRAF6, recruits NEMO/IKKγ to activate the canonical IKK/NF-κB pathway, and simultaneously undergoes proximity-induced dimerization to activate its protease domain, which cleaves a defined set of substrates—including NF-κB inhibitors A20, CYLD, RelB, and HOIL-1, the mRNA stability regulators Roquin-1/2 and Regnase-1, the restriction factor N4BP1, and MALT1 itself—to reinforce and fine-tune NF-κB, JNK/AP-1, and mRNA stability programs critical for lymphocyte activation, Treg development, and immune homeostasis."},"narrative":{"mechanistic_narrative":"MALT1 is a paracaspase that operates at the core of antigen-receptor signaling, functioning dually as a scaffold that drives canonical IKK/NF-κB activation and as an Arg-specific protease that fine-tunes the NF-κB, JNK/AP-1, and mRNA-stability programs underlying lymphocyte activation and immune homeostasis [PMID:14614861, PMID:25456129]. As a scaffold, MALT1 acts downstream of BCL10 to control catalytic activity of the canonical IKK complex and JNK/p38 signaling in a signal-specific manner, being dispensable for TNF-α/IL-1 responses [PMID:14614861]; upon T cell activation it associates with TRAF6, which mediates K63-linked polyubiquitination that recruits NEMO/IKKγ to direct signals to canonical NF-κB [PMID:17948050]. MALT1 cooperatively binds and dimerizes within BCL10 CARD filaments, with TRAF6 decorating these CBM filaments to produce all-or-none higher-order IKK activation [PMID:29382759, PMID:18806265]. Proximity-induced dimerization—rather than cleavage—activates the paracaspase domain, which strictly requires Arg at the substrate P1 position [PMID:22309193]. Its substrates form coherent regulatory circuits: it cleaves the NF-κB inhibitors A20, CYLD, RelB, and the LUBAC subunit HOIL-1 to reinforce or feedback-limit NF-κB and JNK output [PMID:18223652, PMID:21448133, PMID:21873235, PMID:26573773, PMID:27006117], cleaves the mRNA-stability regulators Roquin-1/2 and Regnase-1 to control effector cytokine production [PMID:25456129], cleaves the antiviral RNase N4BP1 to permit HIV-1 latency reactivation [PMID:31133753], and autoproteolytically cleaves itself after Arg-149 to optimize NF-κB target gene expression [PMID:25105596]. MALT1 protease activity is essential for regulatory T cell and innate-like B cell development and for suppressing autoimmunity in a T cell-intrinsic manner, with protease-dead mice developing lethal inflammation and lymphocyte-dependent neurodegeneration [PMID:25456129, PMID:31474984]. MALT1 protease activity is also required for survival of ABC-DLBCL cells, validating it as a therapeutic target [PMID:23238016, PMID:30692685], and aberrant CARD14 mutations engage MALT1 to drive psoriasis-associated keratinocyte inflammation [PMID:27113748].","teleology":[{"year":2003,"claim":"Established MALT1's non-redundant position in antigen-receptor signaling by placing it downstream of BCL10 as a controller of IKK and MAP kinase activation specific to the TCR pathway.","evidence":"Malt1 knockout mouse with T cell activation, IKK activity, and Bcl10/Malt1 epistasis assays","pmids":["14614861"],"confidence":"High","gaps":["Molecular mechanism by which MALT1 activates IKK not resolved","Did not distinguish scaffold vs protease contributions"]},{"year":2005,"claim":"Showed MALT1 shuttles between nucleus and cytoplasm via C-terminal NES and governs BCL10 cytoplasmic localization, adding a spatial regulatory dimension.","evidence":"NES deletion mutants, leptomycin B, subcellular localization microscopy","pmids":["16123224"],"confidence":"Medium","gaps":["Functional significance of nucleocytoplasmic shuttling for signaling unclear","Not connected to downstream NF-κB output"]},{"year":2007,"claim":"Resolved how the TCR scaffold converts into an IKK-activating signal, showing TRAF6 ubiquitinates MALT1 to recruit NEMO toward canonical NF-κB.","evidence":"Co-IP, in vitro ubiquitination, lysine-acceptor mutagenesis, rescue in Malt1-/- T cells","pmids":["17948050"],"confidence":"High","gaps":["Whether ubiquitination also gates protease activity not addressed here","Stoichiometry of NEMO recruitment unknown"]},{"year":2007,"claim":"Separated MALT1 from BCL10 functionally, defining MALT1 as the controller of a c-Rel survival subprogram in B cells distinct from BCL10's broader IKK-recruitment role.","evidence":"Malt1-/- B cells, BCR stimulation, lipid raft IKK fractionation, NF-κB subunit analysis","pmids":["17660823"],"confidence":"High","gaps":["Molecular basis of c-Rel vs RelA selectivity not defined","Protease contribution not isolated"]},{"year":2008,"claim":"Identified the first MALT1 protease substrate, A20, demonstrating MALT1 is an active protease whose cleavage of an NF-κB inhibitor amplifies signaling.","evidence":"Co-IP, in vitro cleavage, cleavage-site mutagenesis, T cell and API2-MALT1 contexts","pmids":["18223652"],"confidence":"High","gaps":["Full substrate repertoire unknown at this stage","Quantitative contribution of A20 cleavage to NF-κB output not measured"]},{"year":2011,"claim":"Expanded the substrate set to CYLD and RelB, linking MALT1 protease activity to TCR-induced JNK activation and canonical NF-κB selectivity.","evidence":"In vitro cleavage, cleavage-site mutagenesis, gene expression profiling, API2-MALT1 overexpression","pmids":["21448133","21873235"],"confidence":"High","gaps":["Relative weight of each substrate in physiological signaling unclear","Kinetics of cleavage in cells not quantified"]},{"year":2012,"claim":"Defined the biochemical mechanism of paracaspase activation—dimerization without cleavage—and its strict Arg-P1 specificity, establishing the enzymatic framework.","evidence":"Recombinant protein, positional-scanning peptide libraries, kinetics, in vitro CYLD cleavage","pmids":["22309193"],"confidence":"High","gaps":["Structural basis of dimerization-induced activation not solved here","In vivo dimerization trigger inferred not directly shown"]},{"year":2012,"claim":"Validated MALT1 protease as a druggable survival dependency by showing MI-2 inhibition kills ABC-DLBCL cells in vitro and in vivo.","evidence":"Direct binding assay, protease activity assay, NF-κB reporter, xenograft model","pmids":["23238016"],"confidence":"High","gaps":["Off-target effects of MI-2 not fully excluded","Resistance mechanisms not explored"]},{"year":2014,"claim":"Demonstrated the physiological essentiality of MALT1 protease activity, revealing protease-dead mice develop lethal autoimmunity and that mRNA-stability regulators are a new substrate class.","evidence":"Protease-dead knock-in mice, Roquin-1/2 and Regnase-1 cleavage, adoptive transfer","pmids":["25456129"],"confidence":"High","gaps":["Cell-type origin of pathology not yet resolved","Interplay between substrate classes not dissected"]},{"year":2014,"claim":"Showed MALT1 auto-cleavage after Arg-149 tunes NF-κB target gene output independent of catalytic activity, distinguishing scaffold-supportive auto-processing from substrate proteolysis.","evidence":"R149A mutagenesis, transcriptome analysis, IκBα phosphorylation, Jurkat rescue","pmids":["25105596"],"confidence":"High","gaps":["Mechanism by which auto-cleavage enhances transcription unclear","Structural consequence of cleavage not defined"]},{"year":2014,"claim":"Defined upstream signalosome organization, showing p62-dependent clustering assembles the Bcl10-Malt1-IKK module prior to IKK activation in effector T cells.","evidence":"p62 knockout T cells, cluster imaging, TAK1/IKK inhibitor epistasis","pmids":["24825920"],"confidence":"Medium","gaps":["Direct p62-MALT1 contacts not mapped","Relationship to TRAF6 ubiquitination unresolved"]},{"year":2015,"claim":"Identified HOIL-1 as a MALT1 substrate generating feedback inhibition of LUBAC, refining how MALT1 cleavage products dampen NF-κB.","evidence":"T cell activation, API2-MALT1, cleavage-product characterization, cleavage-resistant mutant, LUBAC assays","pmids":["26573773","27006117"],"confidence":"Medium","gaps":["Quantitative balance between activating and inhibitory fragments unclear","In vivo relevance not tested with knock-in"]},{"year":2016,"claim":"Connected MALT1 to non-lymphocyte inflammation, showing CARD14 directly binds and activates MALT1 protease in keratinocytes and that psoriasis mutations potentiate this axis.","evidence":"Co-IP, protease activity assay, siRNA, pharmacological inhibition in primary keratinocytes","pmids":["27113748","27071417"],"confidence":"High","gaps":["Endogenous physiological CARD14-MALT1 trigger in skin not defined","In vivo psoriasis rescue by MALT1 inhibition not shown here"]},{"year":2016,"claim":"Revealed isoform-specific control of MALT1 scaffolding, showing exon7 inclusion (MALT1A) augments TRAF6 recruitment and is regulated by hnRNP U during T cell activation.","evidence":"Selective isoform depletion, TRAF6 Co-IP, hnRNP U knockdown","pmids":["27068814"],"confidence":"High","gaps":["Whether protease functions differ between isoforms not fully resolved","Splicing regulatory mechanism left for later work"]},{"year":2018,"claim":"Provided structural insight into signalosome assembly, showing MALT1 dimerizes cooperatively within BCL10 CARD filaments decorated by TRAF6 to yield all-or-none activation.","evidence":"Cryo-EM of BCL10 filament, live imaging of polymerization, in vitro CBM-TRAF6 reconstitution","pmids":["29382759"],"confidence":"High","gaps":["High-resolution structure of MALT1 within the filament absent","Mechanism linking filament geometry to protease activation unclear"]},{"year":2019,"claim":"Established MALT1 protease as an antiviral countermeasure target by showing N4BP1 cleavage at Arg-509 inactivates its RNase and reactivates latent HIV-1.","evidence":"Cleavage assay, mutational analysis, MALT1 knockout, HIV-1 latency reactivation","pmids":["31133753"],"confidence":"High","gaps":["Breadth of N4BP1 RNase targets unknown","Therapeutic implications for latency reversal not tested in vivo"]},{"year":2019,"claim":"Defined the allosteric activation/stabilization mechanism via Trp580 and linked MALT1 loss-of-function to human combined immunodeficiency, plus a corrector strategy.","evidence":"X-ray crystallography, thermal stability, patient W580S lymphocyte signaling rescue","pmids":["30692685"],"confidence":"High","gaps":["Single-patient genetics limits population-level inference","Generalizability of corrector approach untested"]},{"year":2019,"claim":"Added phosphoregulation, showing CK1α-mediated C-terminal serine phosphorylation fosters canonical NF-κB and ABC-DLBCL survival.","evidence":"MS phosphoproteomics, phospho-specific antibodies, CK1α kinase assays, T cell assays","pmids":["31644910"],"confidence":"High","gaps":["Direct effect of phosphorylation on protease vs scaffold not separated","Phosphosite functions individually not dissected"]},{"year":2019,"claim":"Confirmed the T cell-intrinsic autoimmune-suppressive role of MALT1 protease using conditional protease-dead models with full rescue.","evidence":"T cell-conditional protease-dead knock-in, bone marrow reconstitution, human MALT1 rescue","pmids":["31474984"],"confidence":"High","gaps":["Which substrate cleavages drive protection not pinpointed","Contribution of innate cells not addressed"]},{"year":2021,"claim":"Revealed TRAF6's bidirectional role—scaffold-essential for activation yet a homeostatic suppressor of basal MALT1 protease in resting T cells.","evidence":"T cell-specific TRAF6 deletion mice, MALT1-TRAF6 biochemistry, MALT1 inhibitor rescue","pmids":["34767456"],"confidence":"High","gaps":["Molecular mechanism of basal protease suppression unclear","How TRAF6 switches between roles not defined"]},{"year":2022,"claim":"Solved the molecular logic of MALT1 exon7 splicing through competitive hnRNP U/hnRNP L binding to RNA stem-loops controlling U2AF2 recruitment.","evidence":"NMR of RNA stem-loops, RBP interaction studies, splicing reporters, RBP knockdown","pmids":["35921415"],"confidence":"High","gaps":["In vivo physiological control of isoform ratio in disease not tested","Whether other RBPs participate unknown"]},{"year":2023,"claim":"Reinforced CYLD cleavage as a pro-tumor mechanism, linking it to NF-κB-driven lymphoma growth and ibrutinib sensitivity.","evidence":"Protease assay, cleavage-resistant CYLD mutant, IκBα phosphorylation, ibrutinib sensitivity","pmids":["36922488"],"confidence":"Medium","gaps":["Generalizability across lymphoma subtypes not established","Single-lab cleavage-resistant mutant evidence"]},{"year":null,"claim":"How MALT1's reported non-canonical roles (endo-lysosome/autophagy homeostasis, MYC stabilization, c-Jun/GLS1-driven glutaminolysis, neuronal STEP61 degradation) integrate mechanistically with its core paracaspase/scaffold activities remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying substrate or mechanism connects these context-specific roles","Most rest on single-lab pharmacological or knockdown evidence","Direct vs indirect effects not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6,7,9,10,11,16]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,15,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,6,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[24,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,9,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,13,17,29]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,16]}],"complexes":["CBM (CARMA/CARD-BCL10-MALT1) signalosome","BCL10-MALT1-IKK complex"],"partners":["BCL10","TRAF6","A20","CYLD","CARD14","NEMO","CK1A","N4BP1"],"other_free_text":[]}},"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":372,"is_preprint":false},{"pmid":"14614861","id":"PMC_14614861","title":"Differential requirement for Malt1 in T and B cell antigen receptor signaling.","date":"2003","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/14614861","citation_count":311,"is_preprint":false},{"pmid":"23238016","id":"PMC_23238016","title":"MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.","date":"2012","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/23238016","citation_count":224,"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":202,"is_preprint":false},{"pmid":"20685844","id":"PMC_20685844","title":"Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1.","date":"2010","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/20685844","citation_count":193,"is_preprint":false},{"pmid":"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":179,"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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research","url":"https://pubmed.ncbi.nlm.nih.gov/26701346","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48661,"output_tokens":8922,"usd":0.139906,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18935,"output_tokens":6341,"usd":0.1266,"stage2_stop_reason":"end_turn"},"total_usd":0.266506,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"TCR stimulation induces recruitment of A20 into a complex with MALT1 and BCL10, leading to MALT1-mediated proteolytic cleavage of A20 after arginine 439, impairing its NF-κB-inhibitory function. API2-MALT1 fusion also cleaves A20. This identifies A20 as a direct substrate of MALT1 paracaspase activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis of cleavage site, T cell stimulation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro cleavage assay with mutagenesis of cleavage site, replicated in multiple cell contexts including T cells and API2-MALT1-expressing cells\",\n      \"pmids\": [\"18223652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Malt1 is essential for TCR-induced T cell activation, proliferation, and IL-2 production. Malt1 operates downstream of Bcl10 and controls the catalytic activity of the canonical IKK complex, as well as JNK and p38 MAP kinase signaling. Malt1 is dispensable for TNF-α or IL-1 signaling, establishing signal-specific pathway position.\",\n      \"method\": \"Malt1 knockout mouse model, genetic epistasis (Bcl10 vs Malt1 deficiency), T cell activation assays, IKK activity assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts and epistasis analysis, replicated by multiple subsequent studies\",\n      \"pmids\": [\"14614861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MALT1 is polyubiquitinated upon T cell activation. TRAF6 associates with MALT1 after T cell activation and mediates K63-linked polyubiquitination of MALT1 in vitro and in vivo. Ubiquitin chains on MALT1 recruit the IKK regulatory subunit NEMO/IKKγ, directing TCR signals to the canonical NF-κB pathway. Multiple C-terminal lysine residues serve as ubiquitin acceptor sites.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis of lysine acceptor sites, rescue experiments in Malt1-/- T cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution, mutagenesis of acceptor sites, functional rescue in knockout T cells\",\n      \"pmids\": [\"17948050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MALT1 selectively activates c-Rel (but not RelA) downstream of B cell receptor signaling. BCL10 is required for IKK recruitment into lipid rafts and activation of both RelA and c-Rel, whereas MALT1 is dispensable for IKK recruitment and RelA induction but specifically controls a c-Rel subprogram governing survival signaling.\",\n      \"method\": \"Malt1 knockout mouse B cells, BCR stimulation, IKK fractionation into lipid rafts, NF-κB subunit analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal assays distinguishing MALT1 vs BCL10 functions\",\n      \"pmids\": [\"17660823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A20 deubiquitinates MALT1 by removing K63-linked ubiquitin chains, preventing sustained MALT1-IKK interaction and serving as a negative regulator of IKK activity. Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but is dispensable for initial IKK/NF-κB signaling in CD4+ T cells.\",\n      \"method\": \"Antagonistic peptide inhibition, reconstitution in Malt1-/- T cells, TCR/CD28 co-stimulation assays, proteasome inhibition experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary methods (peptide inhibitor, genetic reconstitution) with clear separation of scaffold vs protease functions\",\n      \"pmids\": [\"19494296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Malt1 proteolytically cleaves and inactivates CYLD (a deubiquitinase), which is specifically required for TCR-induced JNK activation and expression of a subset of genes. CYLD cleavage by MALT1 also occurs upon overexpression of oncogenic API2-MALT1.\",\n      \"method\": \"T cell stimulation assays, identification of CYLD as MALT1 substrate, API2-MALT1 overexpression, gene expression profiling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate identification with functional consequence (JNK activation), replicated in oncogenic fusion context\",\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 controlling DNA binding of RelA- and c-Rel-containing NF-κB complexes to promote canonical NF-κB activation in lymphocytes and lymphoma cells.\",\n      \"method\": \"In vitro cleavage assay, site-directed mutagenesis of cleavage site, RelB overexpression, NF-κB reporter and target gene analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage with defined cleavage site, functional rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21873235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MALT1 paracaspase is activated by dimerization without cleavage (analogous to apical caspases). The catalytic domain alone recapitulates full-length MALT1 substrate specificity: strict requirement for Arg at P1 position, with peptide length constraints. Optimal peptidyl substrate cleavage rates (kcat/Km ~10³–10⁴ M⁻¹·s⁻¹) are comparable to caspase-8.\",\n      \"method\": \"Recombinant protein expression/purification, positional-scanning peptidyl substrate libraries, kinetic analysis, in vitro cleavage of CYLD\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro biochemical reconstitution with substrate library screening and kinetic measurements, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22309193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The MALT1 inhibitor MI-2 directly binds MALT1 and irreversibly inhibits its protease function, suppressing ABC-DLBCL cell growth in vitro and in vivo, demonstrating that MALT1 proteolytic activity is essential for ABC-DLBCL cell survival.\",\n      \"method\": \"MALT1 activity assay, direct binding assay, NF-κB reporter, xenotransplant mouse model, cell viability assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, in vitro and in vivo activity, pharmacological validation of protease function\",\n      \"pmids\": [\"23238016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Targeted inactivation of Malt1 paracaspase (protease-dead knock-in mice) causes a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration. Paracaspase activity is essential for Treg and innate-like B cell development. Malt1 cleaves mRNA stability regulators Roquin-1, Roquin-2, and Regnase-1 in addition to NF-κB inhibitors, controlling IFNγ production by effector lymphocytes.\",\n      \"method\": \"Malt1 protease-dead knock-in mouse model, substrate identification (Roquin-1/2, Regnase-1 cleavage), adoptive transfer, in vivo phenotypic analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knock-in model with multiple orthogonal readouts and identification of novel substrate class (mRNA stability regulators)\",\n      \"pmids\": [\"25456129\"],\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 domain) during antigen receptor signaling. This auto-cleavage does not affect proteolytic activity but is required for optimal NF-κB target gene expression (IL-2, CSF2) downstream of nuclear NF-κB accumulation.\",\n      \"method\": \"Site-directed mutagenesis (R149A), transcriptome analysis, IκBα phosphorylation assay, NF-κB reporter, rescue in Jurkat T cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of cleavage site with transcriptome-wide functional validation, single lab multiple orthogonal methods\",\n      \"pmids\": [\"25105596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MALT1 cleaves the LUBAC subunit HOIL-1 in activated T cells. Cleavage generates a C-terminal fragment with LUBAC inhibitory properties, providing gain-of-function negative feedback regulation of NF-κB signaling, while the N-terminal fragment retains HOIP-dependent NF-κB support activity.\",\n      \"method\": \"T cell activation assays, API2-MALT1 overexpression, cleavage product characterization, LUBAC functional assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification with functional characterization of cleavage fragments, single lab\",\n      \"pmids\": [\"26573773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Alternative splicing of MALT1 produces two conserved isoforms (MALT1A containing exon7, MALT1B without). Exon7 inclusion in MALT1A facilitates TRAF6 recruitment, augmenting MALT1 scaffolding function but not protease activity. hnRNP U suppresses exon7 inclusion; naive CD4+ T cells express predominantly MALT1B, and TCR stimulation induces MALT1A expression.\",\n      \"method\": \"Selective isoform depletion, TRAF6 co-immunoprecipitation, T cell signaling assays, hnRNP U knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for TRAF6, selective isoform knockdown with defined signaling readout, multiple orthogonal methods single lab\",\n      \"pmids\": [\"27068814\"],\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 MALT1 protease activation and NF-κB, p38 and JNK signaling. MALT1 deficiency or pharmacological inhibition blocks CARD14 mutant-induced cytokine/chemokine expression in primary keratinocytes.\",\n      \"method\": \"Co-immunoprecipitation, MALT1 protease activity assay, siRNA knockdown, pharmacological inhibition in primary human keratinocytes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction and protease activity demonstrated, multiple complementary approaches in primary human cells\",\n      \"pmids\": [\"27113748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Psoriasis gain-of-function CARD14 mutants constitutively interact with BCL10 and MALT1, trigger BCL10- and MALT1-dependent NF-κB activation in keratinocytes by disrupting the CARD14 linker region autoinhibition. CARD14(E138A) also stimulates MALT1 paracaspase activity and activates ERK1/2 and p38α MAP kinases.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assays, MALT1 protease activity assay, MAP kinase phosphorylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary assays in a single lab, mechanistic dissection of autoinhibition relief\",\n      \"pmids\": [\"27071417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of BCL10 CARD filament at 4.0 Å resolution redefines CARD-CARD interactions. MALT1 cooperatively interacts with BCL10 filaments and immediately dimerizes within the BCL10 filamentous scaffold. TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, producing all-or-none IKK/NF-κB activation.\",\n      \"method\": \"Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, in vitro reconstitution of CBM-TRAF6 filaments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus functional reconstitution and live imaging, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29382759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 cleaves N4BP1 at Arg-509 upon CD4+ T cell activation, inactivating N4BP1's antiviral RNase activity. MALT1-mediated N4BP1 cleavage facilitates reactivation of latent HIV-1 proviruses in T cells.\",\n      \"method\": \"MALT1 cleavage assay, mutational analysis, MALT1 knockout studies, HIV-1 latency reactivation assays\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate cleavage site identified by mutagenesis, confirmed by knockout, functional consequence in viral reactivation demonstrated\",\n      \"pmids\": [\"31133753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An allosteric MALT1 inhibitor binds by displacing the Trp580 side chain, locking MALT1 in an inactive conformation. A patient homozygous for MALT1 W580S mutation suffered combined immunodeficiency due to protein instability; allosteric inhibitors stabilize MALT1-W580S, restoring NF-κB and JNK signaling in patient lymphocytes (molecular corrector mechanism).\",\n      \"method\": \"X-ray crystallography (inhibitor binding mode), thermal stability assays, patient lymphocyte signaling rescue, compound washout/substrate cleavage recovery\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination of inhibitor binding site, functional rescue in patient-derived cells, mechanistic insight into Trp580 role in domain stability\",\n      \"pmids\": [\"30692685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 phosphorylation at multiple serine residues in the C-terminus occurs transiently upon TCR/CD28 co-stimulation via CK1α, which also mediates CBM signalosome assembly. MALT1 phosphorylation fosters canonical NF-κB signaling and promotes survival of ABC-DLBCL cells.\",\n      \"method\": \"Unbiased mass spectrometry phosphoproteomics, phospho-specific antibodies, CK1α kinase assays, Jurkat and primary murine CD4 T cell signaling assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification plus phospho-specific antibody validation plus kinase assignment, multiple cell contexts\",\n      \"pmids\": [\"31644910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAF6 has a dual role: it is indispensable for MALT1 scaffolding-dependent NF-κB signaling in activated T cells, but also counteracts basal MALT1 protease activity in resting T cells. Loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is fully rescued by genetic or pharmacological MALT1 protease inactivation.\",\n      \"method\": \"Genetically engineered mouse models (T cell-specific TRAF6 deletion), biochemical analyses of MALT1-TRAF6 interaction, pharmacological MALT1 inhibition rescue\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models combined with pharmacological rescue and biochemical interaction studies, bidirectional regulation demonstrated\",\n      \"pmids\": [\"34767456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MALT1 contains nuclear export signals (NES) in its C-terminal region and shuttles between the nucleus and cytoplasm in an NES-dependent manner. MALT1 also controls the cytoplasmic localization of BCL10 by promoting its nuclear export.\",\n      \"method\": \"Deletion mutant analysis, leptomycin B treatment (NES inhibitor), subcellular localization by fluorescence microscopy\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mutant analysis and pharmacological NES blockade, localization without full mechanistic pathway connection, single lab\",\n      \"pmids\": [\"16123224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The interaction between BCL10 and MALT1 involves multiple protein domains: the MALT1 death domain and the BCL10 CARD both contribute to the interaction in addition to the previously known Ig-like domain/BCL10 post-CARD region interaction. Residues Asp80 and Glu84 in helix 5 of the BCL10 CARD directly contact MALT1.\",\n      \"method\": \"FRET analysis in T cells, co-immunoprecipitation, point mutagenesis of BCL10 CARD, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP plus mutagenesis in single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"18806265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Bcl10 and Malt1 are required for LPA (lysophosphatidic acid)-induced NF-κB activation downstream of G protein-coupled receptors in non-immune cells (murine embryonic fibroblasts). They cooperate with PKCs selectively for LPA-induced NF-κB but are dispensable for JNK, p38, ERK, and Akt signaling in this context.\",\n      \"method\": \"Bcl10- or Malt1-deficient murine embryonic fibroblasts, LPA stimulation, IκBα degradation assay, MAP kinase and Akt assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout model with signaling pathway specificity established by multiple orthogonal assays\",\n      \"pmids\": [\"17095601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LUBAC subunit HOIL1 is cleaved by MALT1 following antigen receptor engagement in lymphocytes and is constitutively processed in ABC-DLBCL cells. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, identifying HOIL1 as a negative regulator cleaved by MALT1.\",\n      \"method\": \"T cell receptor stimulation assays, MALT1-resistant mutant overexpression, NF-κB reporter, cytokine measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification with functional validation using cleavage-resistant mutant, single lab\",\n      \"pmids\": [\"27006117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A TCR-dependent cytosolic p62-Bcl10-Malt1-IKK signalosome forms in effector T cells. p62-dependent clustering of signaling components stimulates IKK activation and NF-κB translocation. Inhibiting TAK1 or IKK blocks IKK phosphorylation but not p62-Bcl10-Malt1 cluster formation, placing IKK activation after signalosome assembly.\",\n      \"method\": \"Genetic epistasis (p62 knockout T cells), fluorescence microscopy of signalosome clusters, kinase inhibitor treatment, IκBα phosphorylation assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus live imaging plus kinase inhibitor epistasis, single lab\",\n      \"pmids\": [\"24825920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BCL10, MALT1 and IKK inducibly associate with IκBα in a complex distinct from the early CK1α-CBM signalosome during TCR signaling. IκBα knockdown alters BCL10-MALT1 ubiquitylation and impairs MALT1 reorganization into large cytoplasmic structures, suggesting IκBα participates in MALT1 recycling after activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of signalosome components, fluorescence microscopy of MALT1 structures\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and siRNA knockdown, localization studies, single lab with several complementary approaches\",\n      \"pmids\": [\"20551178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MALT1 is an intrinsic regulator of regulatory T cell (Treg) development: Malt1-/- mice have a reduced number of Tregs, with nTregs essentially absent in young mice. iTregs from Malt1-/- mice have higher TLR2 expression and enhanced induction by TLR2 ligands, indicating MALT1 suppresses peripheral iTreg induction during inflammation.\",\n      \"method\": \"Malt1 knockout mouse model, T cell adoptive transfer, in vitro Treg suppression assays, TLR2 ligand stimulation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with multiple immunological readouts, single lab\",\n      \"pmids\": [\"26405015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alternative splicing of MALT1 exon7 is controlled by competitive binding of hnRNP U and hnRNP L to RNA stem-loop structures flanking exon7. hnRNP U stabilizes stem-loop conformations maintaining exon7 skipping (MALT1B); hnRNP L disrupts these structures to facilitate U2AF2 recruitment and exon7 inclusion (MALT1A).\",\n      \"method\": \"NMR structural analysis of RNA stem-loops, RNA binding protein interaction studies, splicing reporter assays, RBP knockdown\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural NMR plus functional splicing assays, mechanism of splice site regulation defined at molecular level, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35921415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 protease activity has a T cell-intrinsic role in suppressing autoimmunity. T cell-conditional protease-dead knock-in mice (Malt1-PDT) phenocopy full-body protease-dead mice, developing ataxia and multi-organ inflammation. Reconstitution of full-body Malt1-PD mice with T cell-specific wild-type human MALT1 eliminates all signs of autoimmunity.\",\n      \"method\": \"T cell-conditional Malt1 protease-dead knock-in mice, bone marrow reconstitution, T cell-specific rescue with human MALT1\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic models with rescue experiment, clear T cell-intrinsic function established\",\n      \"pmids\": [\"31474984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MALT1 controls an MYC-driven gene expression network in mantle cell lymphoma predominantly by increasing MYC protein stability, representing a regulatory mechanism linking BCR/MALT1 signaling to MYC in both MCL and primary mouse splenocytes.\",\n      \"method\": \"MALT1 RNA interference and pharmacological inhibition, gene expression profiling, MYC protein stability assay, primary mouse splenocyte analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with gene expression profiling, mechanism confirmed in primary cells, single lab\",\n      \"pmids\": [\"27864294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MALT1 paracaspase catalytic activity requires activation by monoubiquitination-induced dimerization. Constitutive MALT1 activity in specific B cell lymphoma subsets results from chromosomal translocations or upstream regulatory mutations.\",\n      \"method\": \"Review/summary but grounded in biochemical studies of dimerization and ubiquitination-dependent activation\",\n      \"journal\": \"Current opinion in chemical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper summarizing prior findings, no new primary experimental data\",\n      \"pmids\": [\"25285878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"API2-MALT1 fusion promotes NF-κB activation by binding RIP1 and inducing its ubiquitination at Lys-377. TRAF2 recruitment to the API2 moiety is required for RIP1 ubiquitination and NF-κB activation. This ubiquitination requires the concerted actions of both API2 and MALT1 moieties (gain of function).\",\n      \"method\": \"Co-immunoprecipitation identifying RIP1 as API2-MALT1 binding partner, ubiquitination assays, TRAF2 knockdown, NF-κB reporter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay plus knockdown, single lab\",\n      \"pmids\": [\"23770847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MALT1 protease stabilizes c-Jun by preventing its degradation, supporting GLS1 (glutaminase 1) expression in psoriatic T cells. c-Jun directly binds the GLS1 promoter region, linking MALT1 protease activity to glutaminolysis and Th17 differentiation.\",\n      \"method\": \"MALT1 inhibition in psoriatic CD4+ and γδ T cells, c-Jun stability assay, ChIP assay for c-Jun on GLS1 promoter, metabolic assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus ChIP plus metabolic assays, single lab, mechanistic chain established\",\n      \"pmids\": [\"32831293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MALT1 knockdown or pharmacological inhibition in glioblastoma stem-like cells increases endo-lysosome abundance, impairs autophagic flux, and causes lysosomal-mediated cell death concomitant with mTOR inactivation and dispersal from endo-lysosomes, identifying a role for MALT1 in endo-lysosome homeostasis.\",\n      \"method\": \"MALT1 knockdown, pharmacological inhibitors in vitro and in vivo, lysosome abundance quantification, autophagic flux assays, mTOR localization imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"31774199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MALT1-mediated CYLD cleavage promotes NF-κB signaling and proliferation in BCR-dependent lymphomas. Overexpression of WT CYLD or MALT1-cleavage-resistant CYLD mutant reduces IκBα phosphorylation, represses NF-κB target genes, and impairs lymphoma cell growth. CYLD silencing reduces sensitivity to BTK inhibitor ibrutinib.\",\n      \"method\": \"MALT1 protease assay, MALT1-cleavage-resistant CYLD mutant overexpression, IκBα phosphorylation assay, NF-κB reporter, ibrutinib sensitivity assay\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage-resistant mutant provides clean mechanistic validation, multiple signaling readouts, single lab\",\n      \"pmids\": [\"36922488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HECTD4 E3 ubiquitin ligase mediates MALT1 ubiquitination and degradation. Knockdown of HECTD4 reduces MALT1 ubiquitination, increases MALT1 stability, and promotes GluN2B phosphorylation and calcium overload in neurons via MALT1-dependent STEP61 degradation. MALT1 siRNA counteracts HECTD4 knockdown-induced injury.\",\n      \"method\": \"Co-IP (HECTD4-GluN2B interaction), ubiquitination assays, siRNA knockdown, calcium imaging, ischemic stroke rat model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with genetic rescue, in vivo model, single lab\",\n      \"pmids\": [\"36527595\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MALT1 (PCASP1/MLT) is a paracaspase that functions as both a scaffold protein and an Arg-specific protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome: upon antigen receptor or GPCR stimulation, MALT1 is K63-polyubiquitinated by TRAF6, recruits NEMO/IKKγ to activate the canonical IKK/NF-κB pathway, and simultaneously undergoes proximity-induced dimerization to activate its protease domain, which cleaves a defined set of substrates—including NF-κB inhibitors A20, CYLD, RelB, and HOIL-1, the mRNA stability regulators Roquin-1/2 and Regnase-1, the restriction factor N4BP1, and MALT1 itself—to reinforce and fine-tune NF-κB, JNK/AP-1, and mRNA stability programs critical for lymphocyte activation, Treg development, and immune homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MALT1 is a paracaspase that operates at the core of antigen-receptor signaling, functioning dually as a scaffold that drives canonical IKK/NF-\\u03baB activation and as an Arg-specific protease that fine-tunes the NF-\\u03baB, JNK/AP-1, and mRNA-stability programs underlying lymphocyte activation and immune homeostasis [#1, #9]. As a scaffold, MALT1 acts downstream of BCL10 to control catalytic activity of the canonical IKK complex and JNK/p38 signaling in a signal-specific manner, being dispensable for TNF-\\u03b1/IL-1 responses [#1]; upon T cell activation it associates with TRAF6, which mediates K63-linked polyubiquitination that recruits NEMO/IKK\\u03b3 to direct signals to canonical NF-\\u03baB [#2]. MALT1 cooperatively binds and dimerizes within BCL10 CARD filaments, with TRAF6 decorating these CBM filaments to produce all-or-none higher-order IKK activation [#15, #21]. Proximity-induced dimerization\\u2014rather than cleavage\\u2014activates the paracaspase domain, which strictly requires Arg at the substrate P1 position [#7]. Its substrates form coherent regulatory circuits: it cleaves the NF-\\u03baB inhibitors A20, CYLD, RelB, and the LUBAC subunit HOIL-1 to reinforce or feedback-limit NF-\\u03baB and JNK output [#0, #5, #6, #11, #23], cleaves the mRNA-stability regulators Roquin-1/2 and Regnase-1 to control effector cytokine production [#9], cleaves the antiviral RNase N4BP1 to permit HIV-1 latency reactivation [#16], and autoproteolytically cleaves itself after Arg-149 to optimize NF-\\u03baB target gene expression [#10]. MALT1 protease activity is essential for regulatory T cell and innate-like B cell development and for suppressing autoimmunity in a T cell-intrinsic manner, with protease-dead mice developing lethal inflammation and lymphocyte-dependent neurodegeneration [#9, #28]. MALT1 protease activity is also required for survival of ABC-DLBCL cells, validating it as a therapeutic target [#8, #17], and aberrant CARD14 mutations engage MALT1 to drive psoriasis-associated keratinocyte inflammation [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established MALT1's non-redundant position in antigen-receptor signaling by placing it downstream of BCL10 as a controller of IKK and MAP kinase activation specific to the TCR pathway.\",\n      \"evidence\": \"Malt1 knockout mouse with T cell activation, IKK activity, and Bcl10/Malt1 epistasis assays\",\n      \"pmids\": [\"14614861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which MALT1 activates IKK not resolved\", \"Did not distinguish scaffold vs protease contributions\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed MALT1 shuttles between nucleus and cytoplasm via C-terminal NES and governs BCL10 cytoplasmic localization, adding a spatial regulatory dimension.\",\n      \"evidence\": \"NES deletion mutants, leptomycin B, subcellular localization microscopy\",\n      \"pmids\": [\"16123224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of nucleocytoplasmic shuttling for signaling unclear\", \"Not connected to downstream NF-\\u03baB output\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how the TCR scaffold converts into an IKK-activating signal, showing TRAF6 ubiquitinates MALT1 to recruit NEMO toward canonical NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, lysine-acceptor mutagenesis, rescue in Malt1-/- T cells\",\n      \"pmids\": [\"17948050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ubiquitination also gates protease activity not addressed here\", \"Stoichiometry of NEMO recruitment unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Separated MALT1 from BCL10 functionally, defining MALT1 as the controller of a c-Rel survival subprogram in B cells distinct from BCL10's broader IKK-recruitment role.\",\n      \"evidence\": \"Malt1-/- B cells, BCR stimulation, lipid raft IKK fractionation, NF-\\u03baB subunit analysis\",\n      \"pmids\": [\"17660823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of c-Rel vs RelA selectivity not defined\", \"Protease contribution not isolated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first MALT1 protease substrate, A20, demonstrating MALT1 is an active protease whose cleavage of an NF-\\u03baB inhibitor amplifies signaling.\",\n      \"evidence\": \"Co-IP, in vitro cleavage, cleavage-site mutagenesis, T cell and API2-MALT1 contexts\",\n      \"pmids\": [\"18223652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire unknown at this stage\", \"Quantitative contribution of A20 cleavage to NF-\\u03baB output not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded the substrate set to CYLD and RelB, linking MALT1 protease activity to TCR-induced JNK activation and canonical NF-\\u03baB selectivity.\",\n      \"evidence\": \"In vitro cleavage, cleavage-site mutagenesis, gene expression profiling, API2-MALT1 overexpression\",\n      \"pmids\": [\"21448133\", \"21873235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of each substrate in physiological signaling unclear\", \"Kinetics of cleavage in cells not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the biochemical mechanism of paracaspase activation\\u2014dimerization without cleavage\\u2014and its strict Arg-P1 specificity, establishing the enzymatic framework.\",\n      \"evidence\": \"Recombinant protein, positional-scanning peptide libraries, kinetics, in vitro CYLD cleavage\",\n      \"pmids\": [\"22309193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dimerization-induced activation not solved here\", \"In vivo dimerization trigger inferred not directly shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Validated MALT1 protease as a druggable survival dependency by showing MI-2 inhibition kills ABC-DLBCL cells in vitro and in vivo.\",\n      \"evidence\": \"Direct binding assay, protease activity assay, NF-\\u03baB reporter, xenograft model\",\n      \"pmids\": [\"23238016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target effects of MI-2 not fully excluded\", \"Resistance mechanisms not explored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated the physiological essentiality of MALT1 protease activity, revealing protease-dead mice develop lethal autoimmunity and that mRNA-stability regulators are a new substrate class.\",\n      \"evidence\": \"Protease-dead knock-in mice, Roquin-1/2 and Regnase-1 cleavage, adoptive transfer\",\n      \"pmids\": [\"25456129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of pathology not yet resolved\", \"Interplay between substrate classes not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed MALT1 auto-cleavage after Arg-149 tunes NF-\\u03baB target gene output independent of catalytic activity, distinguishing scaffold-supportive auto-processing from substrate proteolysis.\",\n      \"evidence\": \"R149A mutagenesis, transcriptome analysis, I\\u03baB\\u03b1 phosphorylation, Jurkat rescue\",\n      \"pmids\": [\"25105596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which auto-cleavage enhances transcription unclear\", \"Structural consequence of cleavage not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined upstream signalosome organization, showing p62-dependent clustering assembles the Bcl10-Malt1-IKK module prior to IKK activation in effector T cells.\",\n      \"evidence\": \"p62 knockout T cells, cluster imaging, TAK1/IKK inhibitor epistasis\",\n      \"pmids\": [\"24825920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p62-MALT1 contacts not mapped\", \"Relationship to TRAF6 ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified HOIL-1 as a MALT1 substrate generating feedback inhibition of LUBAC, refining how MALT1 cleavage products dampen NF-\\u03baB.\",\n      \"evidence\": \"T cell activation, API2-MALT1, cleavage-product characterization, cleavage-resistant mutant, LUBAC assays\",\n      \"pmids\": [\"26573773\", \"27006117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative balance between activating and inhibitory fragments unclear\", \"In vivo relevance not tested with knock-in\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected MALT1 to non-lymphocyte inflammation, showing CARD14 directly binds and activates MALT1 protease in keratinocytes and that psoriasis mutations potentiate this axis.\",\n      \"evidence\": \"Co-IP, protease activity assay, siRNA, pharmacological inhibition in primary keratinocytes\",\n      \"pmids\": [\"27113748\", \"27071417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological CARD14-MALT1 trigger in skin not defined\", \"In vivo psoriasis rescue by MALT1 inhibition not shown here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed isoform-specific control of MALT1 scaffolding, showing exon7 inclusion (MALT1A) augments TRAF6 recruitment and is regulated by hnRNP U during T cell activation.\",\n      \"evidence\": \"Selective isoform depletion, TRAF6 Co-IP, hnRNP U knockdown\",\n      \"pmids\": [\"27068814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protease functions differ between isoforms not fully resolved\", \"Splicing regulatory mechanism left for later work\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural insight into signalosome assembly, showing MALT1 dimerizes cooperatively within BCL10 CARD filaments decorated by TRAF6 to yield all-or-none activation.\",\n      \"evidence\": \"Cryo-EM of BCL10 filament, live imaging of polymerization, in vitro CBM-TRAF6 reconstitution\",\n      \"pmids\": [\"29382759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of MALT1 within the filament absent\", \"Mechanism linking filament geometry to protease activation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established MALT1 protease as an antiviral countermeasure target by showing N4BP1 cleavage at Arg-509 inactivates its RNase and reactivates latent HIV-1.\",\n      \"evidence\": \"Cleavage assay, mutational analysis, MALT1 knockout, HIV-1 latency reactivation\",\n      \"pmids\": [\"31133753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of N4BP1 RNase targets unknown\", \"Therapeutic implications for latency reversal not tested in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the allosteric activation/stabilization mechanism via Trp580 and linked MALT1 loss-of-function to human combined immunodeficiency, plus a corrector strategy.\",\n      \"evidence\": \"X-ray crystallography, thermal stability, patient W580S lymphocyte signaling rescue\",\n      \"pmids\": [\"30692685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-patient genetics limits population-level inference\", \"Generalizability of corrector approach untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added phosphoregulation, showing CK1\\u03b1-mediated C-terminal serine phosphorylation fosters canonical NF-\\u03baB and ABC-DLBCL survival.\",\n      \"evidence\": \"MS phosphoproteomics, phospho-specific antibodies, CK1\\u03b1 kinase assays, T cell assays\",\n      \"pmids\": [\"31644910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effect of phosphorylation on protease vs scaffold not separated\", \"Phosphosite functions individually not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the T cell-intrinsic autoimmune-suppressive role of MALT1 protease using conditional protease-dead models with full rescue.\",\n      \"evidence\": \"T cell-conditional protease-dead knock-in, bone marrow reconstitution, human MALT1 rescue\",\n      \"pmids\": [\"31474984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrate cleavages drive protection not pinpointed\", \"Contribution of innate cells not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed TRAF6's bidirectional role\\u2014scaffold-essential for activation yet a homeostatic suppressor of basal MALT1 protease in resting T cells.\",\n      \"evidence\": \"T cell-specific TRAF6 deletion mice, MALT1-TRAF6 biochemistry, MALT1 inhibitor rescue\",\n      \"pmids\": [\"34767456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of basal protease suppression unclear\", \"How TRAF6 switches between roles not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Solved the molecular logic of MALT1 exon7 splicing through competitive hnRNP U/hnRNP L binding to RNA stem-loops controlling U2AF2 recruitment.\",\n      \"evidence\": \"NMR of RNA stem-loops, RBP interaction studies, splicing reporters, RBP knockdown\",\n      \"pmids\": [\"35921415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological control of isoform ratio in disease not tested\", \"Whether other RBPs participate unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reinforced CYLD cleavage as a pro-tumor mechanism, linking it to NF-\\u03baB-driven lymphoma growth and ibrutinib sensitivity.\",\n      \"evidence\": \"Protease assay, cleavage-resistant CYLD mutant, I\\u03baB\\u03b1 phosphorylation, ibrutinib sensitivity\",\n      \"pmids\": [\"36922488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability across lymphoma subtypes not established\", \"Single-lab cleavage-resistant mutant evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MALT1's reported non-canonical roles (endo-lysosome/autophagy homeostasis, MYC stabilization, c-Jun/GLS1-driven glutaminolysis, neuronal STEP61 degradation) integrate mechanistically with its core paracaspase/scaffold activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying substrate or mechanism connects these context-specific roles\", \"Most rest on single-lab pharmacological or knockdown evidence\", \"Direct vs indirect effects not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6, 7, 9, 10, 11, 16]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 15, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 9, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 13, 17, 29]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 16]}\n    ],\n    \"complexes\": [\n      \"CBM (CARMA/CARD-BCL10-MALT1) signalosome\",\n      \"BCL10-MALT1-IKK complex\"\n    ],\n    \"partners\": [\n      \"BCL10\",\n      \"TRAF6\",\n      \"A20\",\n      \"CYLD\",\n      \"CARD14\",\n      \"NEMO\",\n      \"CK1A\",\n      \"N4BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}