RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis.
RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis.
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DOI：
10.1038/s41467-021-27367-5
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发表时间：
2021-12-03
影响因子：
16.6
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Du J;Xiang Y;Liu H;Liu S;Kumar A;Xing C;Wang Z
受体相互作用蛋白激酶1(RIPK1)是炎症和细胞死亡的关键调节因子。RIPK1上的许多位点，包括丝氨酸25，被磷酸化以抑制其激酶活性和细胞死亡。这些抑制的磷酸化位点是如何去磷酸化的还知之甚少。使用致敏的CRISPR全基因组基因敲除筛查，我们发现蛋白磷酸酶1调节亚基3G(PPP1r3G)是RIPK1依赖的细胞凋亡和I型坏死下垂所必需的。从机制上讲，PPP1r3G将催化亚单位蛋白磷酸酶1 γ(pp1γ)招募到复合体I中，以消除RIPK1的抑制磷酸化。PPP1r3G突变体不与PP1RIPK1结合，无法挽救γ激活和细胞死亡。此外，化学预防RIPK1抑制磷酸化或RIPK1丝氨酸25突变为丙氨酸在很大程度上恢复了PPP1r3G基因敲除细胞的细胞死亡。最后，PPP1r3G−/−小鼠被保护免受肿瘤坏死因子诱导的全身炎症反应综合征的影响，证实了PPP1r3G在体内调节细胞凋亡和坏死性下垂的重要作用。RIPK1调节炎症和细胞死亡，并被大量残基的磷酸化抑制。在这里，作者使用CRISPR全基因组筛查来确定蛋白磷酸酶1调节亚基3G调节RIPK1的凋亡和坏死活性以及炎症。
Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole-genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and type I necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1γ) to complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1γ fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g−/− mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo. RIPK1 regulates inflammation and cell death and is inhibited by phosphorylation on numerous residues. Here, the authors use a CRISPR whole genome screen to identify that protein phosphatase 1 regulatory subunit 3G regulates RIPK1 apoptotic and necroptotic activity as well as inflammation.
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