Details
Originalsprache | Englisch |
---|---|
Aufsatznummer | eabh2095 |
Fachzeitschrift | Science Immunology |
Jahrgang | 6 |
Ausgabenummer | 65 |
Publikationsstatus | Veröffentlicht - 12 Nov. 2021 |
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 ?B 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.
ASJC Scopus Sachgebiete
- Medizin (insg.)
- Immunologie und Allergologie
- Immunologie und Mikrobiologie (insg.)
- Immunologie
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in: Science Immunology, Jahrgang 6, Nr. 65, eabh2095, 12.11.2021.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease
AU - O'Neill, Thomas J.
AU - Seeholzer, Thomas
AU - Gewies, Andreas
AU - Gehring, Torben
AU - Giesert, Florian
AU - Hamp, Isabel
AU - Graß, Carina
AU - Schmidt, Henrik
AU - Kriegsmann, Katharina
AU - Tofaute, Marie J.
AU - Demski, Katrin
AU - Poth, Tanja
AU - Rosenbaum, Marc
AU - Schnalzger, Theresa
AU - Ruland, Jürgen
AU - Göttlicher, Martin
AU - Kriegsmann, Mark
AU - Naumann, Ronald
AU - Heissmeyer, Vigo
AU - Plettenburg, Oliver
AU - Wurst, Wolfgang
AU - Krappmann, Daniel
N1 - Funding Information: The work was funded by Helmholtz Zentrum München-German Research Center for Environmental Health. Work of D.K. was supported by Deutsche Forschungsgemeinschaft (ID 210592381 - SFB 1054 A04, ID 360372040 - SFB 1335 P07) and Deutsche Krebshilfe (no. 70112622). V.H. was supported by the Deutsche Forschungsgemeinschaft SPP-1935 and SFB-1054 (ID 210592381 A03) as well as grants from the Wilhelm Sander (no. 2018.082.1) and Deutsche Krebshilfe (no. 70113538) foundations. Work of J.R. was supported by the Deutsche Forschungsgemeinschaft (ID 210592381 - SFB 1054, ID 360372040 - SFB 1335, ID 395357507 - SFB 1371, ID 369799452 - TRR 237, ID 452881907 - TRR 338, RU 695/9-1), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (no. 834154). W.W. was supported by Deutsche Forschungsgemeinschaft SFB 870.
PY - 2021/11/12
Y1 - 2021/11/12
N2 - 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 ?B 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.
AB - 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 ?B 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.
UR - http://www.scopus.com/inward/record.url?scp=85120342806&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.abh2095
DO - 10.1126/sciimmunol.abh2095
M3 - Article
C2 - 34767456
AN - SCOPUS:85120342806
VL - 6
JO - Science Immunology
JF - Science Immunology
SN - 2470-9468
IS - 65
M1 - eabh2095
ER -