p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection

Manoj B Menon; Julia Gropengießer; Jessica Fischer; Lena Novikova; Anne Deuretzbacher; Juri Lafera; Hanna Schimmeck; Nicole Czymmeck; Natalia Ronkina; Alexey Kotlyarov; Martin Aepfelbacher; Matthias Gaestel; Klaus Ruckdeschel

doi:10.1038/ncb3614

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.

Affiliations

¹ Institute of Cell Biochemistry, Hannover Medical School, Hannover 30625, Germany.
² Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, Hamburg 20246, Germany.

PMID: 28920954
DOI: 10.1038/ncb3614

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. p38^MAPK/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 p38^MAPK/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