MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death
- Author(s)
- 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;
- 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
- Research Division(s)
- Cell Signalling And Cell Death; Inflammation
- PubMed ID
- 28506461
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2017.05.003
- Open Access at Publisher's Site
http://www.sciencedirect.com/science/article/pii/S1097276517303167?via%3Dihub- NHMRC Grants
- NHMRC/1025594, NHMRC/1046984, NHMRC/1081221, NHMRC/1081376, NHMRC/1107149, NHMRC/1105754, NHMRC/1081272,
- Terms of Use/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