期刊
MOLECULAR CELL
卷 66, 期 5, 页码 698-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2017.05.003
关键词
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资金
- Breast Cancer Now [CTR-QR14-007]
- World Wide Cancer Research grant [14-1328, 15-0042]
- MRC [MR/M019217/7]
- NHS
- ERC [323040]
- NHMRC [1025594, 1046984, 1081221, 1081376, 1107149, 1105754, 1081272]
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS [9000220]
- Victoria Cancer Agency mid-career fellowship [VCA-MCRF15027]
- BBSRC [BB/L021684/1] Funding Source: UKRI
- MRC [MR/M019217/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L021684/1] Funding Source: researchfish
- Medical Research Council [MR/M019217/1] Funding Source: researchfish
- Worldwide Cancer Research [14-1328] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1081376, 1107149, 9000220, 1081221, 1081272, 1105754] Funding Source: NHMRC
- European Research Council (ERC) [323040] Funding Source: European Research Council (ERC)
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-kappa B, p38 alpha, 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.
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