MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
Details
Publication Year 2017-06-01, Volume 66, Issue #5, Page 698-710
Journal Title
Mol Cell
Publication Type
Journal Article
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-kappaB, p38alpha, 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.
Publisher
Cell Press
WEHI Research Division(s)
Cell Signalling And Cell Death; Inflammation
PubMed ID
28506461
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-05-24 04:06:18
Last Modified: 2017-09-29 11:42:51
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