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
  • 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. [email protected].
  • 11. Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium. [email protected].
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.