K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation
K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation
复制标题
K63 连接的泛素化调节 RIPK1 激酶活性以防止胚胎发生和炎症过程中的细胞死亡
DOI：
10.1038/s41467-019-12033-8
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发表时间：
2019-09-13
影响因子：
16.6
通讯作者：
Lin, Xin
中科院分区：
文献类型：
--
作者：
Tang, Yong;Tu, Hailin;Lin, Xin
Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. However, how its kinase activity is regulated remains poorly understood. Here, we generateRipk1K376R/K376Rknock-in mice in which the Lys(K)63-linked ubiquitination of RIPK1 is impaired. The knock-in mice display an early embryonic lethality due to massive cell death that is resulted from reduced TAK1-mediated suppression on RIPK1 kinase activity and forming more TNFR1 complex II inRipk1K376R/K376Rcells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality ofRipk1K376R/K376Rmice. Notably,Ripk1K376R/-mice are viable but develop severe systemic inflammation that is mainly driven by RIPK3-dependent signaling pathway, indicating that K63-linked ubiquitination on Lys376 residue of RIPK1 also contributes to inflammation process. Together, our study reveals the mechanism by which K63-linked ubiquitination on K376 regulates RIPK1 kinase activity to control cell death programs.
