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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
MALT1 substrate cleavage: What is it good for?
Front. Immunol. 15:1412347 (2024)
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 IκB kinase (IKK)/NF-κB and c-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 have 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.
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Publication type
Article: Journal article
Document type
Review
Keywords
Api2-malt1 ; Cbm Complex ; Malt1 ; Rna Metabolism ; Auto-regulation ; Cell Signaling ; Protease ; Substrate Cleavage; Nf-kappa-b; T-cell-receptor; Paracaspase Malt1; Ubiquitin Ligase; Immune-responses; Messenger-rnas; Activation; Cyld; Roquin; Lubac
ISSN (print) / ISBN
1664-3224
e-ISSN
1664-3224
Journal
Frontiers in Immunology
Quellenangaben
Volume: 15,
Article Number: 1412347
Publisher
Frontiers
Publishing Place
Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Signaling and Translation (SAT)
Grants
Deutsche Forschungsgemeinschaft10.13039/501100001659