Article

MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death

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Abstract

TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.

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Acknowledgements

Research in the groups of M.J.M.B. and P.V. is supported by grants from the Vlaams Instituut voor Biotechnologie (VIB), from the ‘Foundation against Cancer’ (2012-188 and FAF-F/2016/865), from Ghent University (MRP, GROUP-ID consortium), from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (G017212N, G013715N, G078713N), from the Flemish Government (Methusalem BOF09/01M00709 and BOF16/MET_V/007), and from the Belgian science policy office (BELSPO) (IAP 7/32). Y.D. was paid by the agentschap voor Innovatie door Wetenschap en Technologie (IWT), followed by FWO grant G017212N and G013715N, and Methusalem. T.D. and D.P. have a strategic basic research PhD fellowship from the FWO. D.R.-R. is paid by FWO grant G013715N and T.D. is financed by the FWO grant G0A5413N and G0C3714N and Methusalem. F.V.H. was paid by European Consortium Apo-Sys (FP7-HEALTH-2007-A-200767). We thank M. Gaestel (Hannover Medical School, Germany) for the MK2-deficient MEFs and W. Declercq (VIB-UGent) for constructive  discussions.

Author information

Author notes

    • Yves Dondelinger
    •  & Tom Delanghe

    These authors contributed equally to this work.

    • Diego Rojas-Rivera
    •  & Dario Priem

    These authors contributed equally to this work.

Affiliations

  1. Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium

    • Yves Dondelinger
    • , Tom Delanghe
    • , Diego Rojas-Rivera
    • , Dario Priem
    • , Tinneke Delvaeye
    • , Inge Bruggeman
    • , Franky Van Herreweghe
    • , Peter Vandenabeele
    •  & Mathieu J. M. Bertrand
  2. Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium

    • Yves Dondelinger
    • , Tom Delanghe
    • , Diego Rojas-Rivera
    • , Dario Priem
    • , Tinneke Delvaeye
    • , Inge Bruggeman
    • , Franky Van Herreweghe
    • , Peter Vandenabeele
    •  & Mathieu J. M. Bertrand
  3. Physiology Group, Department of Basic Medical Sciences, Ghent University, 9000 Ghent, Belgium

    • Tinneke Delvaeye

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Contributions

Y.D. and M.J.M.B. designed the study. Y.D., T.D., D.R.-R., D.P. and M.J.M.B. designed the experiments. Y.D., T.D., D.R.-R., D.P., T.D., I.B., F.V.H. and M.J.M.B. performed the experiments. M.J.M.B. wrote the manuscript. Y.D., T.D. and P.V. revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mathieu J. M. Bertrand.

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