Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
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DOI：
10.1038/s41467-019-09690-0
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发表时间：
2019-04-15
影响因子：
16.6
通讯作者：
Bertrand, Mathieu J. M.
中科院分区：
文献类型：
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作者：
Dondelinger, Yves;Delanghe, Tom;Bertrand, Mathieu J. M.
RIPK 1通过激酶依赖性和非依赖性机制调节细胞死亡和炎症。作为支架，RIPK 1抑制caspase-8依赖性凋亡和RIPK 3/MLKL依赖性坏死性凋亡。作为一种激酶，RIPK 1矛盾地诱导这些细胞死亡模式。RIPK 1促生存和促死亡功能之间的分子开关仍然知之甚少。我们确定IKKs对Ser 25上的RIPK 1的磷酸化是直接抑制RIPK 1激酶活性和防止TNF介导的RIPK 1依赖性细胞死亡的关键机制。模拟Ser 25磷酸化（S > D突变）在IKK抑制条件下保护细胞和小鼠免受TNF的细胞毒性作用。与它们在IKK激活中的作用一致，TNF诱导的RIPK 1的Ser 25磷酸化在TAK 1或SHARPIN缺陷细胞中是有缺陷的，恢复磷酸化保护这些细胞免受TNF诱导的死亡。重要的是，模拟Ser 25磷酸化损害了耶尔森氏菌感染的体内细胞死亡依赖性免疫控制，这是TAK 1/IKK抑制的生理模型，并挽救了SHARPIN缺陷小鼠的细胞死亡诱导的多器官炎症表型。
RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.