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The proteolytic activity of the paracaspase MALT1 is key in T cell activation

Abstract

The paracaspase MALT1 is pivotal in antigen receptor–mediated lymphocyte activation and lymphomagenesis. MALT1 contains a caspase-like domain, but it is unknown whether this domain is proteolytically active. Here we report that MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor–induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-κB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, which suggests a possible target for the development of immunomodulatory or anticancer drugs.

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Figure 1: Lymphocyte activation induces Bcl-10 cleavage.
Figure 2: Molecular requirements for Bcl-10 cleavage.
Figure 3: MALT1-dependent Bcl-10 cleavage occurs after Arg228.
Figure 4: Recombinant purified MALT1 cleaves the Bcl-10 target sequence in vitro.
Figure 5: Inhibition of the proteolytic activity of MALT1 impairs activation-induced NF-κB and IL-2 responses.
Figure 6: Bcl-10 cleavage regulates the adhesion of T cells to fibronectin but does not affect NF-κB activation.

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Acknowledgements

We thank I. Gonzalez and D. Vercammen for discussions; S. Turcotte and L. Mury for technical assistance; V. Posevitz and P. Romero for culture reagents; A. Golks for technical advice on 'Anderson' gels; and F. Martinon and J. Tschopp for critically reading the manuscript. The plasmid pRDI_292 was a gift from R. Iggo (Swiss Institute for Experimental Cancer Research); Jurkat, Hut78 and Raji cells were gifts from O. Acuto (Pasteur Institute); phycoerythrin-labeled HLA-A*0201 peptide multimers were provided by P. Guillaume and I. Luescher (Ludwig Institute for Cancer Research); silencing vectors targeting the α- and β-subunit of IKK were provided by Y. Refaeli (National Jewish Medical and Research Center); and Jurkat cells deficient in IKKγ (NEMO) and their parental control cells were provided by A. Ting (Mount Sinai School of Medicine). Supported by the Swiss National Science Foundation (M.Th., N.F. and N.R.), the Swiss Cancer League (M.Th.), the Novartis Foundation (M.Th.), the Vontobel Stiftung (M.Th.), Studienstiftung des Deutschen Volkes (S.H.), the Faculty of Biology and Medicine of the University of Lausanne (S.H.) and the Swiss National Center of Competence in Research–Molecular Oncology (N.R.).

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F.R. and S.H. designed, did and analyzed the key experiments; A.P.-F., M.Ta., R.M., O.G. and D.R. did experiments; M.G. provided technical assistance; E.M.I. and N.R. provided human antigen-specific CTLs; N.F. provided new reagents; M.Th. designed and organized the study and wrote the paper; and all authors discussed the results and commented on the manuscript.

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Correspondence to Margot Thome.

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Rebeaud, F., Hailfinger, S., Posevitz-Fejfar, A. et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 9, 272–281 (2008). https://doi.org/10.1038/ni1568

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