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

  • Manoj B Menon (Shared first author)
  • Julia Gropengießer (Shared first author)
  • Jessica Fischer
  • Lena Novikova
  • Anne Deuretzbacher
  • Juri Lafera
  • Hanna Schimmeck
  • Nicole Czymmeck
  • Natalia Ronkina
  • Alexey Kotlyarov
  • Martin Aepfelbacher
  • Matthias Gaestel
  • Klaus Ruckdeschel

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.

Bibliographical data

Original languageEnglish
ISSN1465-7392
DOIs
Publication statusPublished - 10.2017
PubMed 28920954