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

  • Nat Cell Biol. 2017 Oct;19(10):1248-1259. doi: 10.1038/ncb3614.
Manoj B Menon  1 ,  Julia Gropengießer  2 ,  Jessica Fischer  1 ,  Lena Novikova  2 ,  Anne Deuretzbacher  2 ,  Juri Lafera  1 ,  Hanna Schimmeck  2 ,  Nicole Czymmeck  2 ,  Natalia Ronkina  1 ,  Alexey Kotlyarov  1 ,  Martin Aepfelbacher  2 ,  Matthias Gaestel  1 ,  Klaus Ruckdeschel  2
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. 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.

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