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O'Neill, T.J. ; Seeholzer, T. ; Gewies, A. ; Gehring, T. ; Giesert, F. ; Hamp, I. ; Grass, C. ; Schmidt, H.* ; Kriegsmann, K.* ; Tofaute, M.J. ; Demski, K. ; Poth, T.* ; Rosenbaum, M.* ; Schnalzger, T.* ; Ruland, J.* ; Göttlicher, M. ; Kriegsmann, M.* ; Naumann, R.* ; Heissmeyer, V. ; Wurst, W. ; Krappmann, D.

TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease.

Sci. Immunol. 6:eabh2095 (2021)
Postprint Research data DOI
Open Access Green

Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells. In mice, loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is completely reverted by genetic or therapeutic inactivation of MALT1 protease function. Thus, TRAF6 functions as a molecular brake for MALT1 protease in resting T cells and a signaling accelerator for MALT1 scaffolding in activated T cells, revealing that TRAF6 controls T cell activation in a switch-like manner. Our findings have important implications for development and treatment of autoimmune diseases.

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Publication type Article: Journal article
Document type Scientific Article
Keywords Nf-kappa-b; Helper T-cells; Paracaspase Malt1; Crystal-structure; Immune-responses; Ubiquitin Ligase; Messenger-rnas; Activation; Cleavage; Lymphocytes
ISSN (print) / ISBN 2470-9468
e-ISSN 2470-9468
Quellenangaben Volume: 6, Issue: 65, Pages: , Article Number: eabh2095 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC
Reviewing status Peer reviewed
Grants European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program
Deutsche Forschungsgemeinschaft
Deutsche Krebshilfe
Wilhelm Sander Foundation
Deutsche Krebshilfe foundation
Helmholtz Zentrum Munchen-German Research Center for Environmental Health