TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease

Research output: Contribution to journalArticleResearchpeer review

Authors

  • 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

External Research Organisations

  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • Ludwig-Maximilians-Universität München (LMU)
  • Heidelberg University
  • German Cancer Research Center (DKFZ)
  • Max-Planck-Institute of Molecular Cell Biology and Genetics (MPI-CBG)
  • German Center for Neurodegenerative Diseases (DZNE)
  • Technical University of Munich (TUM)
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Details

Original languageEnglish
Article numbereabh2095
JournalScience Immunology
Volume6
Issue number65
Publication statusPublished - 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 subject areas

Cite this

TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. / O'Neill, Thomas J.; Seeholzer, Thomas; Gewies, Andreas et al.
In: Science Immunology, Vol. 6, No. 65, eabh2095, 12.11.2021.

Research output: Contribution to journalArticleResearchpeer review

O'Neill, TJ, Seeholzer, T, Gewies, A, Gehring, T, Giesert, F, Hamp, I, Graß, C, Schmidt, H, Kriegsmann, K, Tofaute, MJ, Demski, K, Poth, T, Rosenbaum, M, Schnalzger, T, Ruland, J, Göttlicher, M, Kriegsmann, M, Naumann, R, Heissmeyer, V, Plettenburg, O, Wurst, W & Krappmann, D 2021, 'TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease', Science Immunology, vol. 6, no. 65, eabh2095. https://doi.org/10.1126/sciimmunol.abh2095
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., ... Krappmann, D. (2021). TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science Immunology, 6(65), Article eabh2095. https://doi.org/10.1126/sciimmunol.abh2095
O'Neill TJ, Seeholzer T, Gewies A, Gehring T, Giesert F, Hamp I et al. TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science Immunology. 2021 Nov 12;6(65):eabh2095. doi: 10.1126/sciimmunol.abh2095
O'Neill, Thomas J. ; Seeholzer, Thomas ; Gewies, Andreas et al. / TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. In: Science Immunology. 2021 ; Vol. 6, No. 65.
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title = "TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease",
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.",
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note = "Funding Information: The work was funded by Helmholtz Zentrum M{\"u}nchen-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. ",
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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.

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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.

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