MK2 phosphorylates RIPK1 to prevent TNF-induced cell death Academic Article uri icon

abstract

  • TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

authors

  • Jaco, Isabel
  • Annibaldi, Alessandro
  • Lalaoui, Najoua
  • Wilson, Rebecca
  • Tenev, Tencho
  • Laurien, Lucie
  • Kim, Chun
  • Jamal, Kunzah
  • Wicky John, Sidonie
  • Liccardi, Gianmaria
  • Chau, Diep
  • Murphy, James M
  • Brumatti, Gabriela
  • Feltham, Rebecca
  • Pasparakis, Manolis
  • Silke, John
  • Meier, Pascal

publication date

  • 2017

has subject area