MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death

Nat Cell Biol. 2017 Oct;19(10):1237-1247. doi: 10.1038/ncb3608. Epub 2017 Sep 18.

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.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Line
  • Cytosol / enzymology
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Necrosis
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / agonists
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Serine
  • Shock / chemically induced*
  • Shock / enzymology
  • Shock / pathology
  • Shock / prevention & control
  • Signal Transduction / drug effects
  • Time Factors
  • Tumor Necrosis Factor-alpha / toxicity*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Serine
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse