MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.

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Date
2017-06Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
HT29 Cells
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Necrosis
Multiprotein Complexes
Protein-Serine-Threonine Kinases
MAP Kinase Kinase Kinases
Tumor Necrosis Factor-alpha
Intracellular Signaling Peptides and Proteins
Mitogen-Activated Protein Kinase 14
NF-kappa B
Transfection
Signal Transduction
Apoptosis
RNA Interference
Phosphorylation
Dose-Response Relationship, Drug
Caspase 8
Fas-Associated Death Domain Protein
Receptor-Interacting Protein Serine-Threonine Kinases
Research team
Cell Death and Immunity
Language
eng
Date accepted
2017-05-03
License start date
2017-06
Citation
Molecular cell, 2017, 66 (5), pp. 698 - 710.e5
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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