MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

被引：266

作者：

Jaco, Isabel ^{[1
]}

Annibaldi, Alessandro ^{[1
]}

Lalaoui, Najoua ^{[2
,3
]}

Wilson, Rebecca ^{[1
]}

Tenev, Tencho ^{[1
]}

Laurien, Lucie ^{[4
,5
,6
]}

Kim, Chun ^{[4
,5
,6
]}

Jamal, Kunzah ^{[1
]}

John, Sidonie Wicky ^{[1
]}

Liccardi, Gianmaria ^{[1
]}

Chau, Diep ^{[2
,3
]}

Murphy, James M. ^{[2
,3
]}

Brumatti, Gabriela ^{[2
,3
]}

Feltham, Rebecca ^{[1
,2
,3
]}

Pasparakis, Manolis ^{[4
,5
,6
]}

Silke, John ^{[2
,3
]}

Meier, Pascal ^{[1
]}

机构：

[1] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, Chester Beatty Labs, Mary Jean Mitchell Green Bldg,Fulham Rd, London SW3 6JB, England

[2] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[3] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

[4] Univ Cologne, Inst Genet, D-50931 Cologne, Germany

[5] Univ Cologne, Ctr Mol Med CMMC, D-50931 Cologne, Germany

[6] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

来源：

MOLECULAR CELL | 2017年 / 66卷 / 05期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 英国生物技术与生命科学研究理事会; 欧洲研究理事会;

关键词：

NF-KAPPA-B; SPATA2 LINKS CYLD; SIGNALING COMPLEX; KINASE-ACTIVITY; UBIQUITIN; INFLAMMATION; ACTIVATION; NECROPTOSIS; APOPTOSIS; TARGET;

D O I：

10.1016/j.molcel.2017.05.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：698 / +

页数：18

共 55 条

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