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

Manoj B Menon1, Julia Gropengießer2, Jessica Fischer1

  • 1Institute of Cell Biochemistry, Hannover Medical School, Hannover 30625, Germany.

Nature Cell Biology
|September 19, 2017
PubMed

Insights

MAPKAP kinase-2 (MK2) phosphorylates Receptor-interacting protein kinase-1 (RIPK1), inhibiting cell death pathways. This crucial checkpoint in inflammation and infection determines bacteria-host cell interaction outcomes.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Receptor-interacting protein kinase-1 (RIPK1) is a key regulator of cell death.
  • Understanding RIPK1 regulation is vital for controlling inflammatory and infectious diseases.

Purpose of the Study:

  • To identify direct substrates of MAPKAP kinase-2 (MK2).
  • To elucidate the role of MK2-mediated RIPK1 phosphorylation in cellular responses to inflammation and infection.

Main Methods:

  • Phosphoproteomic screening of LPS-treated macrophages and stress-stimulated embryonic fibroblasts.
  • Co-immunoprecipitation to study protein interactions.
  • Analysis of cell death pathways (apoptosis and necroptosis) in response to stimuli and pathogen infection.

Main Results:

  • RIPK1 was identified as a direct substrate of MK2.
  • MK2 phosphorylates RIPK1 at Ser321/336 in response to pro-inflammatory stimuli (TNF, LPS) and Yersinia enterocolitica infection.
  • MK2 phosphorylation of RIPK1 inhibits its autophosphorylation, prevents its incorporation into cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis.
  • In Yersinia-infected macrophages, MK2-mediated RIPK1 phosphorylation protects against apoptosis, a process antagonized by Yersinia outer protein P (YopP).

Conclusions:

  • MK2 phosphorylation of RIPK1 is a critical regulatory mechanism controlling cell fate during inflammation and infection.
  • This pathway is essential for determining the outcome of bacteria-host cell interactions and presents a potential therapeutic target.

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