Activity-Based Probes for Detection of Active MALT1 Paracaspase in Immune Cells and Lymphomas
Eitelhuber, Andrea C Vosyka, Oliver Nagel, Daniel Bognar, Miriam Lenze, Dido Lammens, Katja Schlauderer, Florian Hlahla, Daniela Hopfner, Karl-Peter Lenz, Georg Hummel, Michael Verhelst, Steven Krappmann, Daniel # ×
Current Biology Ltd.
Chemistry & Biology vol:22 issue:1 pages:129-38
MALT1 paracaspase is activated upon antigen receptor stimulation to promote lymphocyte activation. In addition, deregulated MALT1 protease activity drives survival of distinct lymphomas such as the activated B cell type of diffuse large B cell lymphoma (ABC-DLBCL). Here, we designed fluorophore or biotin-coupled activity based-probes (ABP) that covalently modify the active center of MALT1. MALT1-ABPs are exclusively labeling an active modified full length form of MALT1 upon T cell stimulation. Further, despite the CARMA1 requirement for initial MALT1 activation, the MALT1-ABPs show that protease activity is not confined to the high-molecular CARMA1-BCL10-MALT1 (CBM) complex. Using biotin-coupled ABPs, we developed a robust assay for sensitive and selective detection of active MALT1 in cell lines, primary lymphocytes, and DLBCL tumor biopsies. Taken together, MALT1-ABPs represent powerful chemical tools to measure cellular MALT1 activation, determine efficacy of small molecule inhibitors, and classify lymphomas based on MALT1 activity status.