1. TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease
- Author
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Oliver Plettenburg, Isabel Hamp, Thomas J. O’Neill, Carina Graß, Daniel Krappmann, Torben Gehring, Marie J. Tofaute, Andreas Gewies, Ronald Naumann, Katrin Demski, Henrik Schmidt, Martin Göttlicher, Florian Giesert, Marc Rosenbaum, Katharina Kriegsmann, Wolfgang Wurst, Thomas Seeholzer, Mark Kriegsmann, Theresa Schnalzger, Jürgen Ruland, Vigo Heissmeyer, and Tanja Poth
- Subjects
T cell ,Immunology ,Inflammation ,TRAF6 protein, mouse ,Biology ,medicine.disease_cause ,Malt1 protein, mouse ,Autoimmunity ,immunology [TNF Receptor-Associated Factor 6] ,Mice ,immunology [Inflammation] ,MALT1 protease ,immunology [Homeostasis] ,genetics [Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein] ,medicine ,Animals ,Homeostasis ,ddc:610 ,TNF Receptor-Associated Factor 6 ,General Medicine ,Acquired immune system ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ,Genetically Engineered Mouse ,immunology [Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein] ,Female ,medicine.symptom ,genetics [TNF Receptor-Associated Factor 6] - Abstract
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.
- Published
- 2021
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