2. Academic Validation
  3. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

  • Nat Commun. 2019 Apr 15;10(1):1729. doi: 10.1038/s41467-019-09690-0.
Yves Dondelinger 1 2,  Tom Delanghe 1 2,  Dario Priem 1 2,  Meghan A Wynosky-Dolfi 3,  Daniel Sorobetea 3,  Diego Rojas-Rivera 1 2 4,  Piero Giansanti 5 6 7,  Ria Roelandt 1 2,  Julia Gropengiesser 8,  Klaus Ruckdeschel 8,  Savvas N Savvides 1 9,  Albert J R Heck 5 6,  Peter Vandenabeele 1 2,  Igor E Brodsky 3,  Mathieu J M Bertrand 10 11
Affiliations

Affiliations

  • 1 VIB Center for Inflammation Research, 9052, Ghent, Belgium.
  • 2 Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium.
  • 3 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4 Center for Integrative Biology (CIB), Faculty of Sciences, Universidad Mayor, 8580745, Santiago, Chile.
  • 5 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CH, Utrecht, The Netherlands.
  • 6 Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands.
  • 7 Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354, Freising, Germany.
  • 8 Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246, Hamburg, Germany.
  • 9 Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium.
  • 10 VIB Center for Inflammation Research, 9052, Ghent, Belgium. mathieu.bertrand@irc.vib-ugent.be.
  • 11 Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium. mathieu.bertrand@irc.vib-ugent.be.
PMID: 30988283 DOI: 10.1038/s41467-019-09690-0
Abstract

RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent Apoptosis and RIPK3/MLKL-dependent Necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia Infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.

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