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MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death


Jaco, I; Annibaldi, A; Lalaoui, N; Wilson, R; Tenev, T; Laurien, L; Kim, C; Jamal, K; Wicky John, S; Liccardi, G; Chau, D; Murphy, JM; Brumatti, G; Feltham, R; Pasparakis, M; Silke, J; Meier, P
2017-06-01
2017-05-10
Mol Cell
Journal Article
66
5
698-710
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.
Cell Press
Cell Signalling and Cell Death ; Inflammation
10.1016/j.molcel.2017.05.003
28506461
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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