Affinage

MALT1

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 · UniProt Q9UDY8

Length
824 aa
Mass
92.3 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2003 High

    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

    PMID:14614861

    Open questions at the time
    • Molecular mechanism by which MALT1 activates IKK not resolved
    • Did not distinguish scaffold vs protease contributions
  2. 2005 Medium

    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

    PMID:16123224

    Open questions at the time
    • Functional significance of nucleocytoplasmic shuttling for signaling unclear
    • Not connected to downstream NF-κB output
  3. 2007 High

    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

    PMID:17948050

    Open questions at the time
    • Whether ubiquitination also gates protease activity not addressed here
    • Stoichiometry of NEMO recruitment unknown
  4. 2007 High

    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

    PMID:17660823

    Open questions at the time
    • Molecular basis of c-Rel vs RelA selectivity not defined
    • Protease contribution not isolated
  5. 2008 High

    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

    PMID:18223652

    Open questions at the time
    • Full substrate repertoire unknown at this stage
    • Quantitative contribution of A20 cleavage to NF-κB output not measured
  6. 2011 High

    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

    PMID:21448133 PMID:21873235

    Open questions at the time
    • Relative weight of each substrate in physiological signaling unclear
    • Kinetics of cleavage in cells not quantified
  7. 2012 High

    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

    PMID:22309193

    Open questions at the time
    • Structural basis of dimerization-induced activation not solved here
    • In vivo dimerization trigger inferred not directly shown
  8. 2012 High

    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

    PMID:23238016

    Open questions at the time
    • Off-target effects of MI-2 not fully excluded
    • Resistance mechanisms not explored
  9. 2014 High

    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

    PMID:25456129

    Open questions at the time
    • Cell-type origin of pathology not yet resolved
    • Interplay between substrate classes not dissected
  10. 2014 High

    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

    PMID:25105596

    Open questions at the time
    • Mechanism by which auto-cleavage enhances transcription unclear
    • Structural consequence of cleavage not defined
  11. 2014 Medium

    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

    PMID:24825920

    Open questions at the time
    • Direct p62-MALT1 contacts not mapped
    • Relationship to TRAF6 ubiquitination unresolved
  12. 2015 Medium

    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

    PMID:26573773 PMID:27006117

    Open questions at the time
    • Quantitative balance between activating and inhibitory fragments unclear
    • In vivo relevance not tested with knock-in
  13. 2016 High

    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

    PMID:27071417 PMID:27113748

    Open questions at the time
    • Endogenous physiological CARD14-MALT1 trigger in skin not defined
    • In vivo psoriasis rescue by MALT1 inhibition not shown here
  14. 2016 High

    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

    PMID:27068814

    Open questions at the time
    • Whether protease functions differ between isoforms not fully resolved
    • Splicing regulatory mechanism left for later work
  15. 2018 High

    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

    PMID:29382759

    Open questions at the time
    • High-resolution structure of MALT1 within the filament absent
    • Mechanism linking filament geometry to protease activation unclear
  16. 2019 High

    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

    PMID:31133753

    Open questions at the time
    • Breadth of N4BP1 RNase targets unknown
    • Therapeutic implications for latency reversal not tested in vivo
  17. 2019 High

    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

    PMID:30692685

    Open questions at the time
    • Single-patient genetics limits population-level inference
    • Generalizability of corrector approach untested
  18. 2019 High

    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

    PMID:31644910

    Open questions at the time
    • Direct effect of phosphorylation on protease vs scaffold not separated
    • Phosphosite functions individually not dissected
  19. 2019 High

    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

    PMID:31474984

    Open questions at the time
    • Which substrate cleavages drive protection not pinpointed
    • Contribution of innate cells not addressed
  20. 2021 High

    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

    PMID:34767456

    Open questions at the time
    • Molecular mechanism of basal protease suppression unclear
    • How TRAF6 switches between roles not defined
  21. 2022 High

    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

    PMID:35921415

    Open questions at the time
    • In vivo physiological control of isoform ratio in disease not tested
    • Whether other RBPs participate unknown
  22. 2023 Medium

    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

    PMID:36922488

    Open questions at the time
    • Generalizability across lymphoma subtypes not established
    • Single-lab cleavage-resistant mutant evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 2
Partners
A20BCL10CARD14CK1ACYLDN4BP1NEMOTRAF6
Complex memberships
BCL10-MALT1-IKK complexCBM (CARMA/CARD-BCL10-MALT1) signalosome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis of cleavage site, T cell stimulation assays Nature immunology High 18223652
2003 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. Malt1 knockout mouse model, genetic epistasis (Bcl10 vs Malt1 deficiency), T cell activation assays, IKK activity assays Immunity High 14614861
2007 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. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis of lysine acceptor sites, rescue experiments in Malt1-/- T cells The EMBO journal High 17948050
2007 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. Malt1 knockout mouse B cells, BCR stimulation, IKK fractionation into lipid rafts, NF-κB subunit analysis Nature immunology High 17660823
2009 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. Antagonistic peptide inhibition, reconstitution in Malt1-/- T cells, TCR/CD28 co-stimulation assays, proteasome inhibition experiments Journal of immunology High 19494296
2011 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. T cell stimulation assays, identification of CYLD as MALT1 substrate, API2-MALT1 overexpression, gene expression profiling The EMBO journal High 21448133
2011 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. In vitro cleavage assay, site-directed mutagenesis of cleavage site, RelB overexpression, NF-κB reporter and target gene analysis Proceedings of the National Academy of Sciences of the United States of America High 21873235
2012 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. Recombinant protein expression/purification, positional-scanning peptidyl substrate libraries, kinetic analysis, in vitro cleavage of CYLD The Biochemical journal High 22309193
2012 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. MALT1 activity assay, direct binding assay, NF-κB reporter, xenotransplant mouse model, cell viability assays Cancer cell High 23238016
2014 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. Malt1 protease-dead knock-in mouse model, substrate identification (Roquin-1/2, Regnase-1 cleavage), adoptive transfer, in vivo phenotypic analysis Cell reports High 25456129
2014 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. Site-directed mutagenesis (R149A), transcriptome analysis, IκBα phosphorylation assay, NF-κB reporter, rescue in Jurkat T cells PloS one High 25105596
2015 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. T cell activation assays, API2-MALT1 overexpression, cleavage product characterization, LUBAC functional assays The FEBS journal Medium 26573773
2016 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. Selective isoform depletion, TRAF6 co-immunoprecipitation, T cell signaling assays, hnRNP U knockdown Nature communications High 27068814
2016 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. Co-immunoprecipitation, MALT1 protease activity assay, siRNA knockdown, pharmacological inhibition in primary human keratinocytes EMBO reports High 27113748
2016 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. Co-immunoprecipitation, NF-κB reporter assays, MALT1 protease activity assay, MAP kinase phosphorylation assays The Biochemical journal Medium 27071417
2018 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. Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, in vitro reconstitution of CBM-TRAF6 filaments Proceedings of the National Academy of Sciences of the United States of America High 29382759
2019 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. MALT1 cleavage assay, mutational analysis, MALT1 knockout studies, HIV-1 latency reactivation assays Nature microbiology High 31133753
2019 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). X-ray crystallography (inhibitor binding mode), thermal stability assays, patient lymphocyte signaling rescue, compound washout/substrate cleavage recovery Nature chemical biology High 30692685
2019 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. Unbiased mass spectrometry phosphoproteomics, phospho-specific antibodies, CK1α kinase assays, Jurkat and primary murine CD4 T cell signaling assays Cell reports High 31644910
2021 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. Genetically engineered mouse models (T cell-specific TRAF6 deletion), biochemical analyses of MALT1-TRAF6 interaction, pharmacological MALT1 inhibition rescue Science immunology High 34767456
2005 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. Deletion mutant analysis, leptomycin B treatment (NES inhibitor), subcellular localization by fluorescence microscopy Blood Medium 16123224
2008 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. FRET analysis in T cells, co-immunoprecipitation, point mutagenesis of BCL10 CARD, molecular modeling The Journal of biological chemistry Medium 18806265
2006 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. Bcl10- or Malt1-deficient murine embryonic fibroblasts, LPA stimulation, IκBα degradation assay, MAP kinase and Akt assays Proceedings of the National Academy of Sciences of the United States of America High 17095601
2016 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. T cell receptor stimulation assays, MALT1-resistant mutant overexpression, NF-κB reporter, cytokine measurement Journal of cell science Medium 27006117
2014 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. Genetic epistasis (p62 knockout T cells), fluorescence microscopy of signalosome clusters, kinase inhibitor treatment, IκBα phosphorylation assays Science signaling Medium 24825920
2010 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. Co-immunoprecipitation, siRNA knockdown of signalosome components, fluorescence microscopy of MALT1 structures Journal of cell science Medium 20551178
2015 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. Malt1 knockout mouse model, T cell adoptive transfer, in vitro Treg suppression assays, TLR2 ligand stimulation Cell death and differentiation Medium 26405015
2022 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). NMR structural analysis of RNA stem-loops, RNA binding protein interaction studies, splicing reporter assays, RBP knockdown Science advances High 35921415
2019 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. T cell-conditional Malt1 protease-dead knock-in mice, bone marrow reconstitution, T cell-specific rescue with human MALT1 Frontiers in immunology High 31474984
2016 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. MALT1 RNA interference and pharmacological inhibition, gene expression profiling, MYC protein stability assay, primary mouse splenocyte analysis Blood Medium 27864294
2015 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. Review/summary but grounded in biochemical studies of dimerization and ubiquitination-dependent activation Current opinion in chemical biology Low 25285878
2013 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). Co-immunoprecipitation identifying RIP1 as API2-MALT1 binding partner, ubiquitination assays, TRAF2 knockdown, NF-κB reporter Oncogene Medium 23770847
2020 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. MALT1 inhibition in psoriatic CD4+ and γδ T cells, c-Jun stability assay, ChIP assay for c-Jun on GLS1 promoter, metabolic assays The Journal of clinical investigation Medium 32831293
2019 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. MALT1 knockdown, pharmacological inhibitors in vitro and in vivo, lysosome abundance quantification, autophagic flux assays, mTOR localization imaging The EMBO journal Medium 31774199
2023 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. MALT1 protease assay, MALT1-cleavage-resistant CYLD mutant overexpression, IκBα phosphorylation assay, NF-κB reporter, ibrutinib sensitivity assay Blood cancer journal Medium 36922488
2022 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. Co-IP (HECTD4-GluN2B interaction), ubiquitination assays, siRNA knockdown, calcium imaging, ischemic stroke rat model Molecular neurobiology Medium 36527595

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nature immunology 372 18223652
2003 Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 311 14614861
2012 MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer cell 224 23238016
2009 A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. Journal of immunology (Baltimore, Md. : 1950) 202 19494296
2010 Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harbor perspectives in biology 193 20685844
2011 Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proceedings of the National Academy of Sciences of the United States of America 190 21873235
2011 T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. The EMBO journal 183 21448133
2007 Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. The EMBO journal 179 17948050
2019 CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nature reviews. Immunology 168 30467369
2003 MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 160 12560219
2014 Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell reports 126 25456129
2014 The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency. The Journal of allergy and clinical immunology 116 25087226
2008 Multifunctional roles for MALT1 in T-cell activation. Nature reviews. Immunology 112 18575460
2020 GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. The Journal of clinical investigation 101 32831293
2015 The paracaspase MALT1: biological function and potential for therapeutic inhibition. Cellular and molecular life sciences : CMLS 97 26507244
2016 Alternative splicing of MALT1 controls signalling and activation of CD4(+) T cells. Nature communications 93 27068814
2004 The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling. Seminars in immunology 92 15541657
2018 Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome. Proceedings of the National Academy of Sciences of the United States of America 88 29382759
2016 MiR-26 down-regulates TNF-α/NF-κB signalling and IL-6 expression by silencing HMGA1 and MALT1. Nucleic acids research 88 27025651
2006 Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production. Proceedings of the National Academy of Sciences of the United States of America 83 17095601
2012 Mechanism and specificity of the human paracaspase MALT1. The Biochemical journal 78 22309193
2017 The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer. Cancer research 74 29259013
2018 Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling. Frontiers in immunology 72 30214442
2015 Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation. Proceedings of the National Academy of Sciences of the United States of America 72 26668357
2010 Regulation of NF-κB signaling by caspases and MALT1 paracaspase. Cell research 71 21119681
2007 MALT1 directs B cell receptor-induced canonical nuclear factor-kappaB signaling selectively to the c-Rel subunit. Nature immunology 71 17660823
2003 Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas. Leukemia 68 12931213
2016 Role of the CARMA1/BCL10/MALT1 complex in lymphoid malignancies. Current opinion in hematology 66 27135977
2016 B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Blood 65 27864294
2014 MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes. PloS one 65 25105596
2016 Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome. Biological chemistry 64 27420898
2019 N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. Nature microbiology 63 31133753
2016 The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes. EMBO reports 61 27113748
2002 BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression. Blood 61 11830492
2016 Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad? Trends in molecular medicine 60 26787500
2019 An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient. Nature chemical biology 56 30692685
2016 Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. The Biochemical journal 55 27071417
2015 MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling. The FEBS journal 55 26573773
2017 The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition. Immunology and cell biology 52 29359407
2015 MALT1 is an intrinsic regulator of regulatory T cells. Cell death and differentiation 52 26405015
2000 Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma. Leukemia 52 11069033
2018 Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth. The Journal of clinical investigation 50 30024860
2016 The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling. Journal of cell science 47 27006117
2015 Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life sciences 46 26135621
2023 Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas. Nature materials 41 36928381
2019 Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis. The EMBO journal 40 31774199
2011 MALT1 protease: a new therapeutic target in B lymphoma and beyond? Clinical cancer research : an official journal of the American Association for Cancer Research 40 21868762
2015 The Paracaspase MALT1. Biochimie 39 26386283
2022 The Gab2-MALT1 axis regulates thromboinflammation and deep vein thrombosis. Blood 38 35895897
2014 T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome. Science signaling 36 24825920
2019 MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner. Frontiers in immunology 35 31474984
2022 Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1. Science advances 34 35921415
2019 Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire. Journal of clinical immunology 34 31037583
2016 MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation. The Journal of investigative dermatology 34 26767426
2008 Multiple protein domains mediate interaction between Bcl10 and MALT1. The Journal of biological chemistry 34 18806265
2005 MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. Blood 34 16123224
2000 Structure of the MLT gene and molecular characterization of the genomic breakpoint junctions in the t(11;18)(q21;q21) of marginal zone B-cell lymphomas of MALT type. Genes, chromosomes & cancer 34 11066071
2018 Ubiquitination and phosphorylation of the CARD11-BCL10-MALT1 signalosome in T cells. Cellular immunology 33 30514565
2010 MLT-10 defines a family of DUF644 and proline-rich repeat proteins involved in the molting cycle of Caenorhabditis elegans. Molecular biology of the cell 33 20335506
2023 Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma. The Journal of clinical investigation 32 36719376
2017 MALT1 promotes melanoma progression through JNK/c-Jun signaling. Oncogenesis 31 28759024
2022 Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency. Journal of clinical immunology 29 35079916
2021 Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL. Blood 29 32785655
2019 MALT1 Phosphorylation Controls Activation of T Lymphocytes and Survival of ABC-DLBCL Tumor Cells. Cell reports 29 31644910
2016 CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis. The Journal of investigative dermatology 29 27939769
2021 TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science immunology 28 34767456
2009 Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives? Cellular signalling 27 19772915
2023 Function and targeting of MALT1 paracaspase in cancer. Cancer treatment reviews 26 37126937
2022 The Paracaspase MALT1 in Cancer. Biomedicines 26 35203553
2015 MALT1 is not alone after all: identification of novel paracaspases. Cellular and molecular life sciences : CMLS 26 26377317
2013 Molecular pathways: targeting MALT1 paracaspase activity in lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 26 24004675
2003 Stability and subcellular localization of API2-MALT1 chimeric protein involved in t(11;18) (q21;q21) MALT lymphoma. Oncogene 26 14603249
2022 MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis. Frontiers in immunology 25 35967391
2021 MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies. Medicinal research reviews 25 33763890
2018 Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions. Frontiers in immunology 25 29881386
2015 Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma. Oncotarget 25 26540570
2013 The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling. Oncogene 24 23770847
2005 Anti-apoptotic action of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma. Apoptosis : an international journal on programmed cell death 24 15711920
2022 Porcine Reproductive and Respiratory Syndrome Virus Adapts Antiviral Innate Immunity via Manipulating MALT1. mBio 23 35467421
2022 Combining precision oncology and immunotherapy by targeting the MALT1 protease. Journal for immunotherapy of cancer 23 36270731
2019 MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging. Frontiers in immunology 23 31632405
2016 MicroRNA-649 promotes HSV-1 replication by directly targeting MALT1. Journal of medical virology 22 27813118
2003 API2-MALT1 fusion gene in colorectal lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 22 14681324
1999 MLT and the immune-hematopoietic system. Advances in experimental medicine and biology 21 10810540
2023 MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. Blood cancer journal 20 36922488
2021 Human MALT1 deficiency and predisposition to infections. Current opinion in immunology 20 33714841
2020 MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice. EMBO reports 20 32343482
2020 A MALT1 inhibitor suppresses human myeloid DC, effector T-cell and B-cell responses and retains Th1/regulatory T-cell homeostasis. PloS one 20 32870913
2016 Development of new Malt1 inhibitors and probes. Bioorganic & medicinal chemistry 20 27085674
2014 Alternative expression pattern of MALT1-A20-NF-κB in patients with rheumatoid arthritis. Journal of immunology research 20 24971370
2015 MALT1-ubiquitination triggers non-genomic NF-κB/IKK signaling upon platelet activation. PloS one 19 25748427
2022 The Weakened Interaction Between HECTD4 and GluN2B in Ischemic Stroke Promotes Calcium Overload and Brain Injury Through a Mechanism Involving the Decrease of GluN2B and MALT1 Ubiquitination. Molecular neurobiology 18 36527595
2022 The combination of gemcitabine and ginsenoside Rh2 enhances the immune function of dendritic cells against pancreatic cancer via the CARD9-BCL10-MALT1 / NF-κB pathway. Clinical immunology (Orlando, Fla.) 18 36581220
2011 Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment. Future oncology (London, England) 17 21568677
2010 Interplay between BCL10, MALT1 and IkappaBalpha during T-cell-receptor-mediated NFkappaB activation. Journal of cell science 17 20551178
2024 MALT1 substrate cleavage: what is it good for? Frontiers in immunology 16 38863711
2024 PRRSV utilizes MALT1-regulated autophagy flux to switch virus spread and reserve. Autophagy 16 39081059
2022 Post-translational modification of MALT1 and its role in B cell- and T cell-related diseases. Biochemical pharmacology 16 35218741
2015 MALT1 Inhibition of Oral Carcinoma Cell Invasion and ERK/MAPK Activation. Journal of dental research 16 26701346
2014 Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase. Current opinion in chemical biology 16 25285878

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