Affinage

MALT1

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

Length
824 aa
Mass
92.3 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MALT1 is a paracaspase that functions as both a scaffold and an arginine-specific cysteine protease within the CARMA/CARD-BCL10-MALT1 (CBM) signalosome, serving as a central integrator of NF-κB activation downstream of antigen receptors, GPCRs, and innate immune receptors in lymphocytes, keratinocytes, and other cell types (PMID:17948050, PMID:17101977, PMID:27113748). As a scaffold, MALT1 undergoes TRAF6-mediated K63-linked polyubiquitination that recruits NEMO/IKKγ for IKK activation, and BCL10 filament-templated MALT1 dimerization cooperatively assembles higher-order signalosomes with TRAF6 for switch-like NF-κB responses; alternative splicing (MALT1A/B) and CK1α-mediated phosphorylation further tune scaffold output (PMID:17948050, PMID:29382759, PMID:27068814, PMID:31644910). Dimerization-dependent protease activity cleaves and inactivates negative regulators of NF-κB—including A20, CYLD, RelB, and HOIL1—after arginine residues, amplifying canonical NF-κB and JNK signaling, while TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells to prevent autoimmunity (PMID:18223652, PMID:21448133, PMID:21873235, PMID:27006117, PMID:34767456). MALT1 protease activity is required for regulatory T cell suppressive function, Th17 differentiation, marginal zone B cell development, and contributes to oncogenic NF-κB in ABC-DLBCL; in keratinocytes, CBM signaling downstream of psoriasis-associated CARD14 mutations drives psoriasiform inflammation (PMID:31138793, PMID:25665967, PMID:34826258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2003 Medium

    Early characterization established that MALT1 is a cytoplasmic protein subject to rapid proteasomal turnover, whereas the oncogenic API2-MALT1 fusion escapes degradation—raising the question of how MALT1 stability is regulated and how the fusion contributes to lymphomagenesis.

    Evidence Subcellular fractionation, proteasome inhibitor treatment, and Western blot stability assays in overexpression systems

    PMID:14603249

    Open questions at the time
    • Single lab, no endogenous protein analysis
    • Mechanism of proteasomal targeting not identified
    • No functional consequence of stabilization tested
  2. 2005 Medium

    Discovery of nuclear export signals in MALT1 revealed that it undergoes constitutive nucleocytoplasmic shuttling and actively maintains BCL10 in the cytoplasm, establishing that MALT1 has a localization-regulatory role beyond signal transduction.

    Evidence Deletion mutants, leptomycin B (NES inhibitor) treatment, and cellular fractionation

    PMID:16123224

    Open questions at the time
    • Single lab observation
    • Functional significance of nuclear shuttling for NF-κB signaling not resolved
    • Endogenous protein shuttling not tracked
  3. 2006 High

    The CBM complex was shown to operate beyond lymphocytes: BCL10 and MALT1 are essential and selective mediators of GPCR-induced NF-κB activation in non-immune cells (fibroblasts, hepatocytes), establishing MALT1 as a broadly utilized NF-κB signaling node.

    Evidence Bcl10−/− and Malt1−/− MEFs and dominant-negative mutants with NF-κB pathway-selective readouts for LPA and angiotensin II stimulation

    PMID:17095601 PMID:17101977

    Open questions at the time
    • Upstream mechanism linking GPCRs to CBM assembly not defined
    • Whether MALT1 protease activity is engaged downstream of GPCRs was untested
  4. 2007 High

    The molecular mechanism linking MALT1 to IKK was resolved: TRAF6-mediated K63-linked polyubiquitination of MALT1 C-terminal lysines creates a docking platform for NEMO/IKKγ, directly connecting CBM assembly to IKK activation.

    Evidence In vitro ubiquitination with recombinant TRAF6, Malt1−/− T cell reconstitution with lysine mutants, IL-2 production

    PMID:17948050

    Open questions at the time
    • Stoichiometry and dynamics of NEMO recruitment not determined
    • Whether other E3 ligases contribute was unknown
  5. 2007 High

    In B cells, MALT1 was found to selectively activate c-Rel without being required for IKK activation or RelA induction, revealing that MALT1 controls a specific NF-κB transcriptional subprogram rather than acting as a generic IKK activator.

    Evidence Malt1−/− B cells with NF-κB subunit-specific DNA-binding and survival assays

    PMID:17660823

    Open questions at the time
    • Mechanism of c-Rel selectivity not determined
    • Whether this selectivity extends to T cells was untested
  6. 2008 High

    MALT1 was identified as an active protease (paracaspase) that cleaves A20 after Arg-439, removing a key NF-κB negative regulator and establishing the paradigm of MALT1 protease-mediated amplification of NF-κB signaling.

    Evidence In vitro cleavage assay, R439 mutagenesis, co-IP of A20 into BCL10-MALT1 complex, NF-κB reporter assays

    PMID:18223652

    Open questions at the time
    • Full substrate repertoire unknown
    • Whether protease activity is essential in vivo was untested
  7. 2009 High

    A reciprocal regulatory circuit was established: A20 deubiquitinates K63-linked chains on MALT1 to limit IKK recruitment, while MALT1 protease cleaves A20, creating a feedback loop that controls NF-κB signaling duration.

    Evidence Malt1−/− T cell reconstitution, ubiquitin chain analysis, IKK activity assays

    PMID:19494296

    Open questions at the time
    • Temporal dynamics of this feedback in vivo not resolved
    • Whether other DUBs target MALT1 was unknown
  8. 2009 High

    MALT1 was shown to participate in non-canonical NF-κB signaling: it is required for BAFF-induced p100 processing and RelB nuclear translocation in marginal zone B cells, interacting with TRAF3 to modulate its levels.

    Evidence Malt1−/− B cells, MALT1-TRAF3 co-IP, NF-κB2 processing assays, BAFF-overexpression in vivo model

    PMID:19917778

    Open questions at the time
    • Whether MALT1 protease activity is required for non-canonical signaling was unclear
    • Mechanism of TRAF3 level regulation by MALT1 not defined
  9. 2011 High

    The substrate repertoire of MALT1 protease expanded to include CYLD (enabling JNK activation) and RelB (enabling canonical NF-κB DNA binding by removing an inhibitory competitor), demonstrating that MALT1 cleavage of multiple negative regulators coordinates NF-κB and JNK pathway activation.

    Evidence In vitro cleavage assays with mutagenesis, Malt1−/− reconstitution, JNK assays, NF-κB DNA-binding assays, DLBCL survival assays

    PMID:21448133 PMID:21873235

    Open questions at the time
    • Relative contribution of each substrate cleavage to NF-κB output not quantified
    • In vivo physiological significance of individual cleavage events untested
  10. 2012 High

    Structural and biochemical studies established that MALT1 protease activity depends on dimerization (not autocleavage), with arginine-directed specificity and kinetics comparable to caspases, and that the C-terminal Ig-like domain is essential for activity.

    Evidence Crystal structure, dimer interface mutagenesis, positional-scanning substrate libraries, kinetic measurements of CYLD cleavage

    PMID:22309193 PMID:22366302

    Open questions at the time
    • Full-length MALT1 structure with BCL10 not available
    • Mechanism of activation at the CBM level not structurally resolved
  11. 2014 High

    MALT1 auto-proteolysis after Arg-149 was identified as a post-activation event that does not regulate catalytic activity per se but is required for optimal NF-κB-dependent transcription, and p62 was found to scaffold the BCL10-MALT1-IKK signalosome in the cytosol.

    Evidence R149A mutagenesis with transcriptome analysis in Jurkat T cells; p62−/− T cells with confocal imaging of signalosome assembly

    PMID:24825920 PMID:25105596

    Open questions at the time
    • How autocleavage enhances transcription mechanistically is unknown
    • Whether p62 scaffolding is cell-type specific was untested
  12. 2015 High

    MALT1 protease-dead knock-in mice revealed that protease activity is essential in vivo for marginal zone/B1 B cell development, T cell proliferation, dendritic cell innate responses, and immune homeostasis, while its scaffolding function alone is insufficient.

    Evidence MALT1 protease-dead knock-in mouse with comprehensive flow cytometry, proliferation assays, immunization, and dendritic cell cytokine assays

    PMID:25665967

    Open questions at the time
    • Relative contribution of individual substrate cleavages to each phenotype not dissected
    • Whether protease-dead mice develop lymphoma or autoimmunity long-term was not fully characterized
  13. 2015 High

    MALT1 was established as a key effector of EGFR-driven oncogenic signaling: it scaffolds TRAF6 recruitment to IKK for NF-κB/STAT3 activation and IL-6 production in EGFR-driven lung tumors, demonstrating CBM pathway cooption by receptor tyrosine kinases in cancer.

    Evidence MALT1 knockdown in cancer cells, Malt1−/− triple-transgenic EGFR-driven lung cancer mouse model, tumor burden analysis

    PMID:25982276

    Open questions at the time
    • Whether MALT1 protease vs. scaffold function drives lung tumorigenesis not separated
    • Applicability to other RTK-driven cancers untested
  14. 2016 High

    Alternative splicing was shown to control MALT1 scaffolding: the MALT1A isoform (exon7-included) facilitates TRAF6 recruitment without altering protease activity, and TCR stimulation induces exon7 inclusion via hnRNP U regulation, adding a splicing-based regulatory layer to CBM signaling.

    Evidence Isoform-selective knockdown, TRAF6 co-IP, hnRNP U knockdown, splicing reporters, T cell activation assays

    PMID:27068814

    Open questions at the time
    • Whether MALT1A/B ratio is dysregulated in disease was not determined
    • How TCR stimulation modulates hnRNP U activity was unclear
  15. 2016 High

    MALT1 substrate repertoire expanded further: HOIL1 (LUBAC subunit) cleavage removes linear ubiquitin chain-generating capacity to amplify NF-κB, and CARD14 was identified as a MALT1 activator in keratinocytes with psoriasis-associated gain-of-function mutations constitutively driving MALT1 protease activity.

    Evidence In vitro cleavage assays, cleavage-resistant HOIL1 rescue, CARD14-MALT1 co-IP and protease activity in primary keratinocytes

    PMID:27006117 PMID:27113748

    Open questions at the time
    • Whether HOIL1 cleavage contributes to ABC-DLBCL pathogenesis in patients was untested
    • Full spectrum of CARD14-MALT1 substrates in keratinocytes unknown
  16. 2018 High

    Cryo-EM revealed the structural basis for CBM signalosome assembly: CARMA1-nucleated BCL10 CARD filaments serve as a template for cooperative MALT1 dimerization and subsequent TRAF6 decoration, explaining the switch-like, all-or-none NF-κB activation behavior.

    Evidence 4.0-Å cryo-EM of BCL10 filament, negative-stain EM of CBM-TRAF6, time-lapse confocal imaging

    PMID:29382759

    Open questions at the time
    • Full atomic-resolution structure of MALT1 on the filament not achieved
    • How filament disassembly/termination occurs is unknown
  17. 2019 High

    Multiple regulatory inputs and functional outputs of MALT1 were defined: CK1α phosphorylates MALT1 C-terminal serines to enhance NF-κB signaling; HECTD3-mediated K27/K29-linked ubiquitination at K648 promotes NF-κB and Th17 differentiation; MALT1 cleaves N4BP1 to relieve HIV-1 latency; and MALT1 protease activity is essential for Treg suppressive function and tumor immune evasion.

    Evidence Mass spectrometry phosphoproteomics with CK1α kinase assays; Hectd3−/− mice with linkage-specific ubiquitination; N4BP1 cleavage assay with HIV-1 reactivation; conditional BCL10 knockout and MALT1 protease-dead mice in melanoma models

    PMID:30741923 PMID:31133753 PMID:31138793 PMID:31644910

    Open questions at the time
    • Integration of phosphorylation and ubiquitination signals on MALT1 not resolved
    • Whether N4BP1 cleavage is relevant beyond HIV latency reversal unknown
    • Therapeutic window for MALT1 inhibition in cancer immunotherapy not defined
  18. 2019 High

    Structural pharmacology of MALT1 was advanced: an allosteric inhibitor locks the protease inactive by displacing Trp580, and this same mechanism rescues the destabilizing W580S patient mutation, demonstrating that allosteric regulation couples protease domain conformation to Ig-like domain interactions.

    Evidence Structural analysis of inhibitor binding, protein stability assays, patient lymphocyte NF-κB/JNK signaling recovery

    PMID:30692685

    Open questions at the time
    • Whether allosteric inhibitors are effective in vivo in disease models not shown in this study
    • Full landscape of loss-of-function MALT1 mutations in immunodeficiency not mapped
  19. 2020 Medium

    MALT1 protease was linked to metabolic reprogramming in Th17 cells: it stabilizes c-Jun by cleavage, promoting GLS1 expression and glutaminolysis that drives H3 acetylation at the Il17a promoter and Th17/γδT17 differentiation in psoriasis.

    Evidence MALT1 inhibitor, c-Jun cleavage assay, ChIP for H3 acetylation, GLS1 analysis, mouse psoriasis models

    PMID:32831293

    Open questions at the time
    • Single lab study
    • Whether metabolic reprogramming by MALT1 extends beyond Th17 cells untested
    • Direct protease cleavage site on c-Jun not mapped
  20. 2021 High

    TRAF6 was revealed to have a dual role: beyond activating NF-κB through MALT1 ubiquitination, TRAF6 homeostatically suppresses basal MALT1 protease activity in resting T cells, and loss of this suppression causes fatal autoimmunity fully rescued by MALT1 protease inactivation.

    Evidence T cell-conditional TRAF6 knockout mice, MALT1 protease measurement in resting vs. activated cells, genetic protease-dead rescue, pharmacological MALT1 inhibitor

    PMID:34767456

    Open questions at the time
    • Molecular mechanism of TRAF6-mediated protease suppression not defined
    • Whether other ubiquitin ligases contribute to basal MALT1 suppression unknown
  21. 2021 High

    Keratinocyte-intrinsic BCL10/MALT1 signaling was established as a driver of psoriasiform inflammation: it amplifies IL-17A/IL-1β/TNF responses and is necessary and sufficient for CARD14 gain-of-function-driven skin disease.

    Evidence Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function model, artificial CBM activating molecules

    PMID:34826258

    Open questions at the time
    • Whether MALT1 protease vs. scaffold function drives skin inflammation not separated
    • Therapeutic efficacy of MALT1 inhibitors in psoriasis patients unknown
  22. 2022 High

    The RNA structural basis of MALT1 alternative splicing was resolved: hnRNP U and hnRNP L competitively bind stem-loop structures flanking exon7, with hnRNP L disrupting these elements to recruit U2AF2 and promote MALT1A expression.

    Evidence NMR structure of regulatory RNA stem-loops, competitive RNA-protein binding assays, splicing reporter assays

    PMID:35921415

    Open questions at the time
    • How TCR activation shifts the hnRNP U/L balance mechanistically remains unknown
    • Whether splicing dysregulation contributes to MALT1-dependent malignancies untested
  23. 2022 Medium

    MALT1 function was extended to endothelial cells: Gab2 facilitates CARMA3-BCL10-MALT1 assembly to mediate IL-1β-induced Rho-dependent exocytosis and NF-κB-driven tissue factor expression, contributing to venous thrombosis.

    Evidence Gab2/MALT1 silencing, pharmacological MALT1 inhibition, P-selectin/VWF exocytosis, IVC ligation DVT mouse model

    PMID:35895897

    Open questions at the time
    • Single lab finding
    • Whether MALT1 protease or scaffold function mediates thrombotic phenotype not resolved
    • Relevance to human venous thromboembolism unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full atomic structure of MALT1 within the assembled CBM filament, the molecular mechanism by which TRAF6 suppresses basal MALT1 protease activity, the complete inventory of MALT1 substrates across cell types, and whether selective MALT1 protease inhibitors can be therapeutically deployed in autoimmunity and cancer without unacceptable immunosuppression.
  • No full-length MALT1-on-filament atomic structure
  • TRAF6 suppression mechanism molecularly undefined
  • Therapeutic index of MALT1 inhibition in patients unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3
Partners
BCL10CARD10CARD11CARD14NEMOSQSTM1TRAF3TRAF6
Complex memberships
BCL10-MALT1 complexCBM signalosome (CARMA/CARD-BCL10-MALT1)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TCR stimulation induces recruitment of A20 into a MALT1-BCL10 complex, leading to MALT1-mediated proteolytic cleavage of A20 after arginine 439, impairing A20's NF-κB-inhibitory function. API2-MALT1 fusion likewise cleaves A20. Co-immunoprecipitation, in vitro cleavage assay, site-directed mutagenesis (R439 cleavage site identification), cell-based NF-κB reporter assays Nature immunology High 18223652
2009 A20 functions as a deubiquitinating enzyme for MALT1, removing K63-linked ubiquitin chains from MALT1 to prevent sustained IKK complex recruitment and limit NF-κB signaling duration after TCR/CD28 stimulation. Reciprocally, MALT1 paracaspase activity cleaves and inactivates A20. Malt1-/- T cell reconstitution, antagonistic peptides, ubiquitin chain analysis, IKK activity assays, IL-2 production measurement Journal of immunology High 19494296
2007 TRAF6 associates with MALT1 upon T cell activation and mediates K63-linked polyubiquitination of MALT1 at multiple C-terminal lysine residues. These ubiquitin chains serve as a docking surface for NEMO/IKKγ recruitment, linking CBM complex formation to IKK/NF-κB activation. Co-immunoprecipitation, in vitro ubiquitination assay with TRAF6 as E3, Malt1-/- T cell reconstitution with ubiquitin-acceptor lysine mutants, IL-2 production readout The EMBO journal High 17948050
2011 MALT1 proteolytically inactivates CYLD, which is required for TCR-induced JNK activation and expression of a subset of JNK-dependent genes. This cleavage is also induced by the oncogenic API2-MALT1 fusion. In vitro cleavage assay, Malt1-/- cell reconstitution, JNK activation assays, gene expression profiling, paracaspase inhibitor treatment The EMBO journal High 21448133
2011 MALT1 cleaves the NF-κB family member RelB after Arg-85, inducing its proteasomal degradation and specifically enabling DNA binding of RelA- and c-Rel-containing NF-κB complexes to drive canonical NF-κB target gene expression. In vitro cleavage assay, site-directed mutagenesis (R85 site), proteasome inhibitor studies, NF-κB DNA-binding assays, DLBCL cell survival assays Proceedings of the National Academy of Sciences of the United States of America High 21873235
2012 MALT1 protease activity is dependent on dimerization; the unliganded protease exists as a dimer in an inactive state and undergoes substantial conformational changes upon substrate binding. The C-terminal Ig-like domain is required for MALT1 activity. Dimer interface mutations abrogate protease activity in cells. Crystal structure determination, biochemical dimerization assays, mutagenesis of dimer interface, cell-based protease activity assays Journal of molecular biology High 22366302
2012 MALT1 paracaspase cleaves specifically after arginine residues with stringent peptide length constraints. Dimerization activates both full-length MALT1 and its catalytic domain without cleavage, analogous to apical caspases. CYLD is cleaved by MALT1 with kcat/Km values comparable to optimal peptidyl substrates. Positional-scanning peptidyl substrate libraries, recombinant protein expression and purification, in vitro kinetic assays, dimerization studies The Biochemical journal High 22309193
2014 MALT1 undergoes auto-proteolytic cleavage after Arg-149 (between the death domain and first Ig-like region) upon antigen receptor stimulation. This autocleavage does not affect protease activity but is required for optimal NF-κB-dependent transcription of target genes (IL-2, CSF2) downstream of nuclear NF-κB accumulation. Site-directed mutagenesis (R149A), Jurkat T cell reconstitution, NF-κB reporter assays, transcriptome analysis, IκBα phosphorylation assays PloS one High 25105596
2018 Cryo-EM structure of BCL10 CARD filament at 4.0-Å resolution shows CARMA1 nucleates unidirectional BCL10 polymerization. MALT1 cooperatively interacts with BCL10 filaments and immediately dimerizes on the filamentous scaffold. TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies for all-or-none downstream pathway activation. Cryo-EM structure determination, time-lapse confocal imaging of BCL10 polymerization, pulldown assays, negative-stain EM Proceedings of the National Academy of Sciences of the United States of America High 29382759
2006 CARMA3-BCL10-MALT1 mediates angiotensin II receptor (GPCR)-induced NF-κB activation in non-immune hepatocytes, acting through IKKγ ubiquitination. Dominant-negative mutants, RNAi, or gene targeting of any CBM component abolishes Ang II-dependent NF-κB activation. Dominant-negative mutants, RNAi knockdown, Bcl10-/- mouse embryonic fibroblasts, NF-κB reporter assays, cytokine production measurement in vivo Proceedings of the National Academy of Sciences of the United States of America High 17101977
2006 BCL10 and MALT1 are essential mediators of lysophosphatidic acid (LPA)-induced NF-κB activation downstream of G protein-coupled receptors in non-immune fibroblasts, cooperating with PKCs selectively for NF-κB but dispensable for JNK, p38, ERK, and Akt pathways. Bcl10-/- and Malt1-/- mouse embryonic fibroblasts, IκBα degradation assays, NF-κB activation assays, kinase pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 17095601
2007 MALT1 selectively activates c-Rel but not RelA in B cells after BCR stimulation. MALT1 participates in survival signaling but is not required for IKK recruitment into lipid rafts, IKK activation, or RelA induction, demonstrating selective control of a c-Rel-dependent transcriptional subprogram. Malt1-/- B cells, lipid raft fractionation, NF-κB subunit-specific assays, cell survival and proliferation assays Nature immunology High 17660823
2016 MALT1 alternative splicing generates two conserved isoforms: MALT1A (exon7-included) and MALT1B. MALT1A facilitates TRAF6 recruitment, augmenting MALT1 scaffolding function but not protease activity. hnRNP U suppresses exon7 inclusion; TCR stimulation induces MALT1A expression. Selective MALT1A depletion impairs T cell signaling and activation. Isoform-selective knockdown, Co-immunoprecipitation of TRAF6, NF-κB signaling assays, hnRNP U knockdown, T cell activation assays Nature communications High 27068814
2019 MALT1 proteolytically cleaves N4BP1 (an HIV-1 restriction factor with RNase activity) at Arg-509 upon T cell activation, inactivating N4BP1's ability to degrade viral mRNA and thereby facilitating reactivation of latent HIV-1 proviruses. RNA-binding protein screen, N4BP1 cleavage assay, MALT1 knockout/knockdown studies, HIV-1 reactivation assay, mutational analysis of cleavage site Nature microbiology High 31133753
2016 CARD14 physically interacts with MALT1 and activates MALT1 proteolytic activity in keratinocytes. Psoriasis-associated CARD14 mutations enhance this interaction constitutively, driving BCL10- and MALT1-dependent NF-κB, p38, and JNK activation, and inflammatory gene expression. Co-immunoprecipitation, MALT1 protease activity assays, MALT1 siRNA/inhibitor studies, primary human keratinocyte assays with psoriasis-mutant CARD14 EMBO reports High 27113748
2016 MALT1 cleaves the LUBAC subunit HOIL1 upon antigen receptor engagement. HOIL1 is constitutively processed in ABC-DLBCL cells with aberrant MALT1 activity. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, identifying HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1. In vitro cleavage assay, MALT1 inhibitor treatment, overexpression of cleavage-resistant HOIL1 mutant, NF-κB reporter assay, cytokine measurement Journal of cell science High 27006117
2005 MALT1 contains nuclear export signal (NES) sequences in its C-terminal region, causing constitutive nucleocytoplasmic shuttling. MALT1 regulates cytoplasmic localization of BCL10 through this NES-dependent export mechanism. Deletion mutant analysis, leptomycin B treatment (NES inhibitor), cellular fractionation and localization studies Blood Medium 16123224
2009 MALT1 is required for BAFF-induced non-canonical NF-κB signaling (phosphorylation of NF-κB2/p100, p100 degradation, RelB nuclear translocation) in marginal zone B cells. MALT1 interacts with TRAF3, a negative regulator of BAFF receptor signaling, and MALT1 deficiency results in elevated TRAF3 levels. Malt1-/- B cells, Co-immunoprecipitation (MALT1-TRAF3), NF-κB2 processing assays, B cell survival assays, in vivo BAFF-overexpression model The Journal of experimental medicine High 19917778
2008 BCL10-MALT1 interaction involves multiple protein domains: the Ig-like domains of MALT1 interact with a post-CARD region of BCL10, but the MALT1 death domain and BCL10 CARD also contribute. FRET analysis identified the MALT1 death domain contribution in live T cells. BCL10 CARD residues Asp80 and Glu84 in helix 5 directly contact MALT1. Co-immunoprecipitation, FRET analysis in T cells, BCL10 point mutant analysis, molecular modeling The Journal of biological chemistry Medium 18806265
2019 TRAF6 plays a dual role: it recruits to MALT1 for NF-κB signaling in activated T cells, but also counteracts basal MALT1 protease activity in resting T cells. Loss of TRAF6-mediated homeostatic suppression leads to severe autoimmune inflammation fully rescued by MALT1 protease inactivation. Genetically engineered mouse models (T cell-specific TRAF6 knockout), biochemical MALT1 protease activity assays, pharmacological MALT1 inhibitor rescue, autoimmune phenotype analysis Science immunology High 34767456
2019 MALT1 protease is constitutively active in psoriatic CD4+ and γδ T cells and stabilizes c-Jun by proteolytic cleavage, thereby supporting GLS1 (glutaminase 1) expression. This promotes glutaminolysis, H3 acetylation at the Il17a promoter, and Th17/γδT17 cell differentiation contributing to psoriasis. MALT1 inhibitor treatment, c-Jun cleavage assay, chromatin immunoprecipitation (H3 acetylation), GLS1 expression analysis, mouse psoriasis models The Journal of clinical investigation Medium 32831293
2019 BCL10-controlled MALT1 paracaspase activity is essential for the immune-suppressive function of regulatory T cells (Tregs) but not for their differentiation per se. In tumor models, acute genetic BCL10 blockade in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. T cell-conditional BCL10 knockout mice, MALT1 protease-dead knock-in mice, melanoma mouse models, Treg suppression assays Nature communications High 31138793
2015 MALT1 protease-dead knock-in mice reveal that MALT1 protease activity is required for marginal zone and B1 B cell development, T cell proliferation and IL-2 production, dendritic cell cytokine responses to Dectin-1/2/Mincle, and immune homeostasis. Protease-dead mice develop mixed inflammatory cell infiltrates in multiple organs. MALT1 protease-dead knock-in mouse generation, flow cytometry of lymphocyte subsets, proliferation assays, in vivo immunization, dendritic cell cytokine assays PloS one High 25665967
2014 TCR signals to NF-κB are transmitted through a cytosolic p62-BCL10-MALT1-IKK signalosome. p62 is required for clustering of BCL10-MALT1 with IKK in effector T cells. TAK1 and IKK inhibition block IKK phosphorylation but not signalosome assembly, indicating IKK activation occurs after signalosome formation. Confocal imaging of signalosome assembly, p62-/- T cells, kinase inhibitor studies, co-immunoprecipitation Science signaling Medium 24825920
2019 The E3 ubiquitin ligase HECTD3 promotes K27-linked and K29-linked non-degradative polyubiquitination of MALT1 at K648, which is required for NF-κB activation and Th17 cell differentiation in experimental autoimmune encephalomyelitis. Hectd3-/- mice, ubiquitination assays with linkage-specific antibodies, Malt1 K648 mutagenesis, NF-κB activation assays, Th17 differentiation assays Nature communications Medium 30741923
2019 MALT1 phosphorylation at multiple C-terminal serine residues occurs after TCR/CD28 co-stimulation, mediated by CK1α. CK1α is essential for both CBM signalosome assembly and MALT1 phosphorylation. MALT1 phosphorylation is largely dispensable for protease activity but fosters canonical NF-κB signaling and promotes survival of ABC-DLBCL cells. Unbiased mass spectrometry phosphoproteomics, phospho-specific antibody generation, CK1α kinase assays, genetic and pharmacological CK1α inhibition, Jurkat/primary CD4 T cell NF-κB assays Cell reports High 31644910
2019 An allosteric MALT1 inhibitor binds by displacing the side chain of Trp580, locking the protease in an inactive conformation. Loss of Trp580 (W580S patient mutation) weakens interactions between the paracaspase and C-terminal Ig-like domains causing protein instability; allosteric inhibitor binding rescues W580S MALT1 stability and restores NF-κB/JNK signaling in patient lymphocytes. Structural analysis of inhibitor binding mode, biochemical protein stability assays, patient lymphocyte NF-κB/JNK signaling assays, MALT1 substrate cleavage recovery after compound washout Nature chemical biology High 30692685
2003 The API2-MALT1 fusion protein is stable compared to wild-type MALT1 (which is rapidly degraded via the ubiquitin-proteasome pathway). Both MALT1 and API2-MALT1 are localized exclusively in the cytoplasm. Subcellular fractionation, Western blot stability assays, proteasome inhibitor treatment, deletion mutant analysis Oncogene Medium 14603249
2022 hnRNP U and hnRNP L competitively bind stem-loop RNA structures flanking MALT1 exon7. hnRNP U stabilizes RNA stem-loop conformations maintaining exon7 skipping (MALT1B), while hnRNP L disrupts these elements to recruit splicing factor U2AF2 and promote exon7 inclusion (MALT1A). NMR structure of RNA stem-loops, RNA-protein binding assays, competitive binding studies, splicing reporter assays, U2AF2 recruitment analysis Science advances High 35921415
2015 MALT1 is required for EGFR-induced NF-κB activation in cancer cells, functioning mainly as a scaffold protein by recruiting TRAF6 to the IKK complex. MALT1 deficiency abolished both NF-κB and STAT3 activation in EGFR-driven lung tumors in vivo, attributed to defective IL-6 production. MALT1 knockdown in cancer cells, triple-transgenic EGFR-driven lung cancer mouse model (Malt1-/-), NF-κB/STAT3 activation assays, IL-6 production measurement, tumor burden analysis Oncogene High 25982276
2022 Gab2 facilitates assembly of the CARMA3-BCL10-MALT1 signalosome in endothelial cells. MALT1 within this complex mediates IL-1β-induced Rho-dependent exocytosis of P-selectin and von Willebrand factor, NF-κB-dependent tissue factor expression, and neutrophil adhesion. MALT1 inhibition or Gab2 silencing suppresses venous thrombosis in mice. Gene silencing (Gab2, MALT1), MALT1 pharmacological inhibition (mepazine), P-selectin/VWF exocytosis assays, Rho activity assays, inferior vena cava ligation DVT mouse model Blood Medium 35895897
2021 TRAF6 recruits to MALT1 in activated T cells and is indispensable for NF-κB signaling, but also counteracts basal MALT1 protease activity in resting T cells via a homeostatic suppression mechanism. Loss of this suppression leads to fatal autoimmune inflammation fully reversed by MALT1 protease inactivation. T cell-conditional TRAF6 knockout mice, MALT1 protease activity measurement in resting vs. activated T cells, MALT1 protease-dead genetic rescue, pharmacological MALT1 inhibitor treatment Science immunology High 34767456
2021 Keratinocyte-intrinsic BCL10/MALT1 signaling amplifies responses to IL-17A, IL-1β, and TNF and is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation. Selective keratinocyte BCL10/MALT1 deletion completely rescues Card14 gain-of-function-driven skin pathology. Keratinocyte-conditional BCL10/MALT1 knockout mice, Card14 gain-of-function mouse model, artificial BCL10/MALT1 activating engager molecule, cytokine response assays, skin inflammation scoring Science immunology High 34826258

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 371 18223652
2009 A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. Journal of immunology (Baltimore, Md. : 1950) 200 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 177 17948050
2019 CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nature reviews. Immunology 166 30467369
2003 MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 159 12560219
2000 Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas. The American journal of pathology 157 10751343
2000 The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. The American journal of pathology 154 10751367
2006 CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proceedings of the National Academy of Sciences of the United States of America 149 17101977
2014 The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency. The Journal of allergy and clinical immunology 115 25087226
2008 Multifunctional roles for MALT1 in T-cell activation. Nature reviews. Immunology 110 18575460
2020 GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. The Journal of clinical investigation 99 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 86 29382759
2018 The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex. Frontiers in immunology 85 30283440
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
2015 Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. Journal of clinical immunology 80 25627829
2012 Structural determinants of MALT1 protease activity. Journal of molecular biology 79 22366302
2023 Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages. Journal of experimental & clinical cancer research : CR 77 36797769
2012 Mechanism and specificity of the human paracaspase MALT1. The Biochemical journal 77 22309193
2015 MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses. PloS one 76 25965667
2006 The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2. The Journal of biological chemistry 75 16891304
2019 Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. Nature communications 74 31138793
2017 The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer. Cancer research 74 29259013
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
2019 Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation. Nature communications 71 30741923
2018 Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling. Frontiers in immunology 71 30214442
2007 MALT1 directs B cell receptor-induced canonical nuclear factor-kappaB signaling selectively to the c-Rel subunit. Nature immunology 71 17660823
2010 Regulation of NF-κB signaling by caspases and MALT1 paracaspase. Cell research 70 21119681
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
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
2016 Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad? Trends in molecular medicine 60 26787500
2007 CARD-Bcl10-Malt1 signalosomes: missing link to NF-kappaB. Science's STKE : signal transduction knowledge environment 58 17473310
2015 MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression. Oncogene 56 25982276
2019 An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient. Nature chemical biology 55 30692685
2016 Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. The Biochemical journal 55 27071417
2017 The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition. Immunology and cell biology 52 29359407
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
2017 MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia. Cancer research 49 28993409
2017 miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma. Cancer letters 48 28286260
2016 The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling. Journal of cell science 47 27006117
2009 Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets. The Journal of experimental medicine 47 19917778
2015 Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life sciences 46 26135621
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
2019 Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis. The EMBO journal 39 31774199
2023 Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas. Nature materials 38 36928381
2015 The Paracaspase MALT1. Biochimie 38 26386283
2022 The Gab2-MALT1 axis regulates thromboinflammation and deep vein thrombosis. Blood 36 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
2020 Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology. Frontiers in immunology 34 32425939
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
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
2020 MALT1 is a potential therapeutic target in glioblastoma and plays a crucial role in EGFR-induced NF-κB activation. Journal of cellular and molecular medicine 30 32452133
2019 MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types. Oncogene 30 31420608
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
2022 Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency. Journal of clinical immunology 28 35079916
2021 TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science immunology 28 34767456
2016 CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis. The Journal of investigative dermatology 28 27939769
2023 Function and targeting of MALT1 paracaspase in cancer. Cancer treatment reviews 26 37126937
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 The Paracaspase MALT1 in Cancer. Biomedicines 25 35203553
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
2021 MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies. Medicinal research reviews 24 33763890
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
2014 Probes to monitor activity of the paracaspase MALT1. Chemistry & biology 23 25556944
2023 Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway. European journal of pharmacology 22 37146710
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 22 10810540
2022 Allicin suppressed Escherichia coli-induced urinary tract infections by a novel MALT1/NF-κB pathway. Food & function 21 35246671
2022 Combining precision oncology and immunotherapy by targeting the MALT1 protease. Journal for immunotherapy of cancer 21 36270731
2021 Human MALT1 deficiency and predisposition to infections. Current opinion in immunology 20 33714841
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
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
2021 Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation. Science immunology 16 34826258
2019 Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer. International journal of cancer 16 31291468
2018 MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain. Journal of virology 16 29367251
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