TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease

Thomas J. O’Neill, Thomas Seeholzer, Andreas Gewies, Torben Gehring, Florian Giesert, Isabel Hamp, Carina Graß, Henrik Schmidt, Katharina Kriegsmann, Marie J. Tofaute, Katrin Demski, Tanja Poth, Marc Rosenbaum, Theresa Schnalzger, Jürgen Ruland, Martin Göttlicher, Mark Kriegsmann, Ronald Naumann, Vigo Heissmeyer, Oliver Plettenburg, Wolfgang Wurst, Daniel Krappmann (12 Nov 2021) TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science Immunology 6 eabh 2095. DOI: 10.1126/sciimmunol.abh2095 (Projects A03, A04, B01)

Abstract cited from the publication:

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 lymphatic tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor kB 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.