Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates

Bell, Peter A.; Scheuermann, Sophia; Renner, Florian; Pan, Christina L.; Lu, Henry Y.; Turvey, Stuart E.; Bornancin, Frédéric; Régnier, Catherine H.; Overall, Christopher M.

doi:10.1016/j.csbj.2022.08.021

Cited by 10 publications

(15 citation statements)

References 59 publications

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“…MALT1 belongs to the family of cysteine proteases and the PCASP domain shows a high structural homology to caspases, but in contrast to their aspartate-specific protease activity, MALT1 recognizes a distinct set of substrates cleaved after arginine residues ( 29 ). While most initial discoveries of MALT1 substrates relied on serendipity, a bioinformatic workflow confirmed and extended our knowledge to approximately 20-30 MALT1 substrates ( 30 ). MALT1 substrates control diverse cellular processes involved in signaling (CYLD, A20, HOIL-1), transcription (RelB), mRNA metabolism (Regnase-1, Roquin-1/2, N4BP1), CBM auto-regulation (CARD10, BCL10, MALT1) and adhesion (Tensin-3), suggesting interdependent and independent functions of the MALT1 protease and scaffold ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 54%

MALT1 substrate cleavage: what is it good for?

Moud,

Ober,

O’Neill

et al. 2024

Front. Immunol.

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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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Section: Introductionmentioning

confidence: 54%

MALT1 substrate cleavage: what is it good for?

Moud,

Ober,

O’Neill

et al. 2024

Front. Immunol.

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“…We show that RBPs Roquin-1/2 are also cleaved by MALT1 in ABC DLBCL, and other RNA regulators such as N4BP1 and Regnase-4/ZC3H12D have been identified as MALT1 substrates. 59 , 60 Putative functions for DLBCL pathogenesis need to be determined, but the data indicate that MALT1 protease modulates the activity of multiple factors involved in posttranscriptional gene regulation. Posttranscriptional events are also governing gene induction by oncogenic API2-MALT1.…”

Section: Discussionmentioning

confidence: 99%

Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas

Wimberger,

Ober,

Avar

et al. 2023

Blood

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Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data hint that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of many genes including NFKBIZ/IkBz, NFKBID/IkBNS and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.

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“…The protease activity of MALT1 facilitates optimal NF-κB and AP-1 activation by proteolytic cleavage of negative regulators, such as A20, CYLD and RELB. Other MALT1 substrates regulate mRNA stability (Regnase-1, Roquin-1) [ 18 , 19 , 20 ]. Upon surface receptor activation, CARMA/CARD, BCL10 and MALT1 form the CBM complex serving as a protein assembly platform for NF-κB activation [ 17 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing

Wittner

Wagener

Wiese

et al. 2023

IJMS

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The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear. In this study, we investigate the role of MALT1 proteolytic activity in the context of mucosal inflammation. We demonstrate a significant enrichment of MALT1 gene and protein expression in colonic epithelial cells of UC patients, as well as in the context of experimental colitis. Mechanistically we demonstrate that MALT1 protease function inhibits ferroptosis, a form of iron-dependent cell death, upstream of NF-κB signaling, which can promote inflammation and tissue damage in IBD. We further show that MALT1 activity contributes to STAT3 signaling, which is essential for the regeneration of the intestinal epithelium after injury. In summary, our data strongly suggests that the protease function of MALT1 plays a critical role in the regulation of immune and inflammatory responses, as well as mucosal healing. Understanding the mechanisms by which MALT1 protease function regulates these processes may offer novel therapeutic targets for the treatment of IBD and other inflammatory diseases.

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Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates

Cited by 10 publications

References 59 publications

MALT1 substrate cleavage: what is it good for?

MALT1 substrate cleavage: what is it good for?

Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing

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