p38 MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection

Nat Cell Biol. 2017 Oct;19(10):1248-1259. doi: 10.1038/ncb3614. Epub 2017 Sep 18.

Abstract

Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Bacterial Proteins / metabolism
  • Cytosol / enzymology
  • Cytosol / microbiology
  • Female
  • Genotype
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • I-kappa B Kinase / metabolism
  • Inflammation / enzymology*
  • Inflammation / pathology
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinases / metabolism
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Macrophages / microbiology
  • Macrophages / pathology
  • Male
  • Membrane Proteins / metabolism
  • Mice, Knockout
  • Necrosis
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Serine
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / toxicity
  • Yersinia Infections / enzymology*
  • Yersinia Infections / microbiology
  • Yersinia Infections / pathology
  • Yersinia enterocolitica / metabolism
  • Yersinia enterocolitica / pathogenicity*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Bacterial Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Yop proteins translocation protein P, Yersinia
  • Serine
  • MAP-kinase-activated kinase 2
  • MAP-kinase-activated kinase 3
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7