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The protease activity of the paracaspase MALT1 is controlled by monoubiquitination

Nature Immunology volume 14, pages 337–345 (2013)Cite this article

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Abstract

The protease activity of the paracaspase MALT1 is central to lymphocyte activation and lymphomagenesis, but how this activity is controlled remains unknown. Here we identify a monoubiquitination of MALT1 on Lys644 that activated the protease function of MALT1. Monoubiquitinated MALT1 had enhanced protease activity, whereas a ubiquitination-deficient MALT1 mutant with replacement of that lysine with arginine (MALT1(K644R)) had less protease activity, which correlated with impaired induction of interleukin 2 (IL-2) via the T cell antigen receptor in activated T cells. Expression of MALT1(K644R) diminished the survival of cells derived from diffuse large B cell lymphoma of the activated B cell–like subtype (ABC DLBCL), which require constitutive protease activity of MALT1 for survival. Thus, monoubiquitination of MALT1 is essential for its catalytic activation and is therefore a potential target for the treatment of ABC-DLBCL and for immunomodulation.

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Figure 1: MALT1 is monoubiquitinated after stimulation of T cells.
Figure 2: MALT1 is monoubiquitinated on Lys644 in HEK293T cells.
Figure 3: Monoubiquitination is required and sufficient for the protease activity of MALT1.
Figure 4: The protease activity of MALT1 depends on functional ubiquitin.
Figure 5: The C-terminal domain of MALT1 regulates its protease activity.
Figure 6: Monoubiquitination of MALT1 is important for NF-κB activation in T cells.
Figure 7: Monoubiquitination of MALT1 in ABC DLBCL.

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Acknowledgements

We thank S. Valitutti (Centre Hospitalier Universitaire Purpan) for monoclonal antibody OKT3; R. Iggo (University of Bordeaux) for lentiviral vector pRDI_292 containing the EF1 promoter; J.-E. Charton (University of Lausanne) for purified T cells; M. Jaworski (University of Lausanne) for the lentiviral NF-κB reporter construct; Z. Chen (University of Texas Southwestern Medical Center) for ubiquitin mutants; N. Clipstone (Loyola University) for the pMSCV-IRES-GFP vector; K. Maslowski for manuscript corrections; S. Hailfinger for support and advice; K. Hofmann and I. Dikic for advice; and F. Martinon for critical reading of the manuscript. Supported by the Swiss National Science Foundation, the Swiss Cancer League (Oncosuisse), Fondation Pierre Mercier Pour la Science, Fondation Emma Muschamp, a collaboration agreement with Ono Pharmaceutical, the Boehringer Ingelheim Foundation (K.C.), the German Research Foundation (G.L.) and the Deutsche Krebshilfe (G.L.).

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Authors and Affiliations

  1. Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, Epalinges, Switzerland

    Christiane Pelzer, Katrin Cabalzar, Montserrat Gonzalez & Margot Thome

  2. Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité–Universitätsmedizin Berlin, Germany

    Annette Wolf & Georg Lenz

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  1. Christiane Pelzer
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Contributions

C.P. designed and did experiments, analyzed data and wrote the manuscript; K.C. and A.W. contributed to the experiments in Figures 5 and 7d, respectively; M.G. provided technical assistance; G.L. designed and analyzed experiments in Figure 7d and M.T. designed and organized the study and wrote the paper.

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Correspondence to Margot Thome.

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Part of the work by C.P., K.C., M.G. & M.T. was supported by a collaboration agreement with Ono Pharmaceutical.

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Pelzer, C., Cabalzar, K., Wolf, A. et al. The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nat Immunol 14, 337–345 (2013). https://doi.org/10.1038/ni.2540

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