MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.
MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death.
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DOI：
10.1016/j.molcel.2017.05.003
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发表时间：
2017-06-01
期刊：
影响因子：
16
通讯作者：
Meier P
中科院分区：
文献类型：
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作者：
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
TNF是一种炎性细胞因子，在与其受体TNFR 1结合后，可以驱动细胞因子产生、细胞存活或细胞死亡。TNFR 1刺激引起NF-κB、p38α及其下游效应激酶MK 2的活化，从而促进靶基因的转录、mRNA稳定和翻译。在这里，我们表明，TNF诱导的MK2激活的结果在全球RIPK 1磷酸化。MK 2直接磷酸化RIPK 1的残基S321，抑制其结合FADD/半胱天冬酶-8和诱导RIPK 1激酶依赖性细胞凋亡和坏死性凋亡的能力。因此，磷酸化模拟S321 D RIPK 1突变限制了TNF诱导的死亡。从机制上讲，我们发现S321的磷酸化抑制了RIPK 1激酶的激活。我们进一步表明，胞质RIPK 1有助于复合物II介导的细胞死亡，独立于其招聘到复合物I，这表明复合物II起源于复合物I和胞质RIPK 1中的RIPK 1。因此，MK 2介导的RIPK 1磷酸化作为TNF信号通路内的检查点，整合细胞存活和细胞因子产生。MK2对RIPK 1的磷酸化在TNF信号传导中充当存活检查点。TNF诱导的MK2活化导致RIPK 1的整体磷酸化。MK2介导的磷酸化抑制RIPK 1激酶活化和细胞死亡。显示MK2在残基S321处直接磷酸化RIPK 1，抑制RIPK 1的细胞毒性潜力，并在TNF信号传导途径中充当检查点。
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. Phosphorylation of RIPK1 by MK2 acts as survival checkpoint in TNF signaling TNF-induced activation of MK2 results in global RIPK1 phosphorylation MK2-mediated phosphorylation suppresses RIPK1 kinase activation and cell death Complex-II originates from RIPK1 in complex-I as well as cytosolic RIPK1 Jaco et al. show that MK2 directly phosphorylates RIPK1 at residue S321, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway.