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T cell antigen receptor stimulation induces MALT1 paracaspase–mediated cleavage of the NF-κB inhibitor A20

Nature Immunology volume 9, pages 263–271 (2008)Cite this article

Abstract

The paracaspase MALT1 mediates T cell antigen receptor–induced signaling to the transcription factor NF-κB and is indispensable for T cell activation and proliferation. Enhanced expression of MALT1 or aberrant expression of a fusion protein of the apoptosis inhibitor API2 and MALT1 has been linked to mucosa-associated lymphoid tissue lymphoma. Despite the presence of a caspase-like domain, MALT1 proteolytic activity has not yet been demonstrated. Here we show that T cell antigen receptor stimulation induced recruitment of the NF-κB inhibitor A20 into a complex of MALT1 and the adaptor protein Bcl-10, leading to MALT1-mediated processing of A20. API2-MALT1 expression likewise resulted in cleavage of A20. MALT1 cleaved human A20 after arginine 439 and impaired its NF-κB-inhibitory function. Our studies identify A20 as a substrate of MALT1 and emphasize the importance of MALT1 proteolytic activity in the 'fine tuning' of T cell antigen receptor signaling.

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Figure 1: Generation of a 37-kDa fragment of A20 after activation of T cells and B cells.
Figure 2: MALT1 interacts with A20 and is essential for its proteolytic cleavage.
Figure 3: A20 is cleaved by MALT1.
Figure 4: Human A20 is processed by MALT1 at R439.
Figure 5: Mouse and human A20 are processed at distinct sites.
Figure 6: Cleavage of A20 by MALT1 disrupts its inhibitory effect on TCR-induced activation of NF-κB.
Figure 7: Inhibition of the proteolytic activity of MALT1 or AP12-MALT1 decreases MALT1-mediated NF-κB activation and IL-2 production.

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Acknowledgements

We thank D. Vlieghe and P. Hulpiau for help with the alignment of caspase-like molecules; J. Phillipe (Ghent University, Belgium) and M. Dyer (University of Leicester, UK) for gifts of the Jurkat and SSK41 cell lines, respectively; and S. Janssens and D. Vercammen for discussions. Supported by the 'Interuniversity Attraction Poles' (IAP6/18 to R.B. and IAP5/25 to P.M.), 'Fonds voor Wetenschappelijk Onderzoek-Vlaanderen' (3G010505 to R.B. and G050704 to P.M.), King Baudouin Foundation (Alphonse and Jean Forton Fund; R.B.), Ghent University (Concerted Action Grant 01G06B6 to R.B.) and Catholic University Leuven (Concerted Action Grant to P.M.).

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Author notes

  1. Beatrice Coornaert and Mathijs Baens: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Molecular Biology, Ghent University, Ghent, B-9052, Belgium

    Beatrice Coornaert, Karen Heyninck, Tine Bekaert, Mira Haegman, Jens Staal & Rudi Beyaert

  2. Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Flanders Institute for Biotechnology, Ghent, B-9052, Belgium

    Beatrice Coornaert, Karen Heyninck, Tine Bekaert, Mira Haegman, Jens Staal & Rudi Beyaert

  3. Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, Catholic University Leuven, Leuven, B-3000, Belgium

    Mathijs Baens & Peter Marynen

  4. Department of Molecular and Developmental Genetics, Human Genome Laboratory, Flanders Institute for Biotechnology, Leuven, B-3000, Belgium

    Mathijs Baens & Peter Marynen

  5. Department of Molecular Biology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Lijun Sun & Zhijian J Chen

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Contributions

B.C., M.B., K.H., T.B., M.H. and J.S. did the experiments; L.S. and Z.J.C. provided recombinant MALT1; B.C., M.B. and R.B. wrote the paper; B.C., M.B., K.H. and R.B. designed the experiments; and R.B. and P.M. supervised the experiments, offered scientific advice and share senior authorship.

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Correspondence to Rudi Beyaert.

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Coornaert, B., Baens, M., Heyninck, K. et al. T cell antigen receptor stimulation induces MALT1 paracaspase–mediated cleavage of the NF-κB inhibitor A20. Nat Immunol 9, 263–271 (2008). https://doi.org/10.1038/ni1561

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