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The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition

Bardet, Maureen and Unterreiner, Adeline and Malinverni, Claire and Lafossas, Frederique and Vedrine, Corinne and Boesch, Danielle and Kolb, Yeter and Kaiser, Daniel and Glueck, Anton and Schneider, Martin Alexander and Katopodis, Andreas and Renatus, Martin and Simic, Oliver and Schlapbach, Achim and Quancard, Jean and Regnier, Catherine and Bold, Guido and Pissot Soldermann, Carole and Carballido, Jose and Kovarik, Jiri and Calzascia, Thomas and Bornancin, Frederic (2018) The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition. Immunology and cell biology.

Abstract

MALT1 is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T cell activation and fate after engagement of the T cell receptor pathway. We show that MLT-827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T cell activation, in contrast to the pan-protein kinase C inhibitor AEB071. However, MLT-827 strongly impacted survival after activation. We demonstrate this is the consequence of profound inhibition of IL-2 production as well as reduced expression of the high affinity IL-2 receptor (CD25), resulting from defective canonical NF-κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT-827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T cell signaling pathways. Altogether, this first report with a potent and selective MALT1 inhibitor elucidates that MALT1 paracaspase activity indirectly controls gamma-chain receptor dependent signaling, which is required for T cell proliferation and clonal expansion.

Item Type: Article
Date Deposited: 29 May 2018 00:45
Last Modified: 29 May 2018 00:45
URI: https://oak.novartis.com/id/eprint/33099

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