MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2017-06-01
Date Accepted
2017-05-03
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.
Citation
Molecular cell, 2017, 66 (5), pp. 698 - 710.e5
Source Title
Publisher
CELL PRESS
ISSN
1097-2765
eISSN
1097-4164
Collections
Research Team
Cell Death and Immunity