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REVIEW article

Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1412347
This article is part of the Research Topic Community Series in CARMA Proteins: Playing a Hand of Four CARDs: Volume II View all articles

MALT1 substrate cleavage: What is it good for?

Provisionally accepted
Bahareh Nemati Moud Bahareh Nemati Moud Franziska Ober Franziska Ober Thomas J. O'Neill Thomas J. O'Neill Daniel Krappmann Daniel Krappmann *
  • Molecular Targets and Therapeutics Center, Helmholtz Center München, Helmholtz Association of German Research Centres (HZ), Neuherberg, Germany

The final, formatted version of the article will be published soon.

    CARD-BCL10-MALT1 (CBM) signalosomes connect distal signaling of innate and adaptive immune receptors to proximal signaling pathways and immune activation. Four CARD scaffold proteins (CARD9,10,11,14) can form seeds that nucleate the assembly of BCL10-MALT1 filaments in a cell-and stimulus-specific manner. MALT1 (also known as PCASP1) serves a dual function within the assembled CBM complexes. By recruiting TRAF6, MALT1 acts as a molecular scaffold that initiates IB kinase (IKK)/NF-B and Jun N-terminal kinase (JNK)/AP-1 signaling. In parallel, proximity-induced dimerization of the paracaspase domain activates the MALT1 protease which exerts its function by cleaving a set of specific substrates. While complete MALT1 ablation leads to immune deficiency, selective destruction of either scaffolding or protease function provokes autoimmune inflammation. Thus, balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation. Further, MALT1 protease activity drives the survival of aggressive lymphomas and other non-hematologic solid cancers. However, little is known about the relevance of the cleavage of individual substrates for the pathophysiological functions of MALT1. Unbiased serendipity, screening and computational predictions identified and validated ~20 substrates, indicating that MALT1 targets a quite distinct set of proteins. Known substrates are involved in CBM auto-regulation (MALT1, BCL10 and CARD10), regulation of signaling and adhesion (A20, CYLD, HOIL-1 and Tensin-3), or transcription (RelB) and mRNA stability/translation (Regnase-1, Roquin-1/2 and N4BP1), indicating that MALT1 often targets multiple proteins involved in similar cellular processes. Here, we will summarize what is known about the fate and functions of individual MALT1 substrates and how their cleavage contributes to the biological functions of the MALT1 protease. We will outline what is needed to better connect critical pathophysiological roles of the MALT1 protease with the cleavage of distinct substrates.

    Keywords: Self-cleavage resistant, T6BM: TRAF6 binding motifs, TAB3: TAK1 binding protein 3, TAD: Transcriptional activation domain, TANK: TRAF family member associated NF-B activator, TBM: TRAF6-binding mutant, TCR: T cell antigen receptor, TLR: toll-like receptor

    Received: 04 Apr 2024; Accepted: 07 May 2024.

    Copyright: © 2024 Nemati Moud, Ober, O'Neill and Krappmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Daniel Krappmann, Molecular Targets and Therapeutics Center, Helmholtz Center München, Helmholtz Association of German Research Centres (HZ), Neuherberg, Germany

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