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

  • Yves Dondelinger
  • Tom Delanghe
  • Dario Priem
  • Meghan A Wynosky-Dolfi
  • Daniel Sorobetea
  • Diego Rojas-Rivera
  • Piero Giansanti
  • Ria Roelandt
  • Julia Gropengiesser
  • Klaus Ruckdeschel
  • Savvas N Savvides
  • Albert J R Heck
  • Peter Vandenabeele
  • Igor E Brodsky
  • Mathieu J M Bertrand

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.

Bibliographical data

Original languageEnglish
ISSN2041-1723
DOIs
Publication statusPublished - 15.04.2019
PubMed 30988283