Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation.
Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation.
复制标题
酪氨酸磷酸化调节 RIPK1 活性以限制细胞死亡和炎症
DOI：
10.1038/s41467-022-34080-4
复制
发表时间：
2022-11-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
受体相互作用丝氨酸/苏氨酸蛋白激酶1 （RIPK1）是一种调节多种炎症和细胞死亡途径的细胞质蛋白激酶。已知RIPK1的丝氨酸/苏氨酸磷酸化在炎症、感染和胚胎发生的情况下抑制RIPK1激酶介导的细胞死亡，然而，酪氨酸磷酸化的调控尚未报道。在这里，我们发现非受体酪氨酸激酶Janus kinase 1 （JAK1）和SRC能够磷酸化RIPK1的Y384位点（小鼠RIPK1的Y383位点），从而抑制tnf诱导的细胞死亡。携带可阻止Ripk1酪氨酸磷酸化的纯合子Ripk1突变（Ripk1Y383F/Y383F）的小鼠，会发生全身性炎症和紧急造血。机制上，Ripk1Y383F/Y383F突变促进RIPK1激酶激活，增强tnf诱导的细胞凋亡和坏死坏死，部分原因是MAP激酶活化蛋白激酶2 （MK2）的募集和激活受损。RIPK1激酶抑制可在很大程度上缓解Ripk1Y383F/Y383F小鼠的全身炎症和紧急造血，并可通过靶向上游途径（肿瘤坏死因子受体1或同时靶向RIPK3和Caspase8）的基因组缺失来阻止。总之，我们的研究结果表明，酪氨酸磷酸化RIPK1对于调节RIPK1活性以限制细胞死亡和炎症至关重要。受体相互作用丝氨酸/苏氨酸蛋白激酶1 （RIPK1）是胚胎发生和感染/炎症过程中细胞死亡途径的重要调节因子。本文作者表明，上游激酶对RIPK1的酪氨酸磷酸化限制了全身炎症并调节了造血稳态。
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of cell death pathways during embryogenesis and in infection/inflammation. Here authors show that tyrosine phosphorylation of RIPK1 by upstream kinases limits systemic inflammation and regulates haematopoietic homeostasis.
登录
查看更多内容
TNF-α 和 IFN-γ 信号之间的串扰诱导肝细胞癌细胞中 B7-H1 表达
影响因子：
5.8
作者：
Li, Na;Wang, Jianing;Shi, Yongyu
通讯作者：
Shi, Yongyu
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
通过TAK1介导的磷酸化来调节RIPK1激活，决定了凋亡和坏死性。
影响因子：
16.6
作者：
Geng J;Ito Y;Shi L;Amin P;Chu J;Ouchida AT;Mookhtiar AK;Zhao H;Xu D;Shan B;Najafov A;Gao G;Akira S;Yuan J
通讯作者：
Yuan J