K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation

• Published in: Nature communications Vol. 10; no. 1; pp. 4157 - 15
• Main Authors: Tang, Yong, Tu, Hailin, Zhang, Jie, Zhao, Xueqiang, Wang, Yini, Qin, Jun, Lin, Xin
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.09.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Apoptosis; Cell death; Cell Death - genetics; Cell Death - physiology; Clonal deletion; Embryogenesis; Embryonic Development - genetics; Embryonic Development - physiology; Embryonic growth stage; Flow Cytometry; HEK293 Cells; Humans; Immunoprecipitation; Inflammation; Inflammation - genetics; Inflammation - metabolism; Kinases; Lethality; Mice; Molecular Biology - methods; Mortality; Protein kinase; Real-Time Polymerase Chain Reaction; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Signal transduction; TAK1 protein; Tumor necrosis factor receptors; Tumor necrosis factor-α; Ubiquitination; Ubiquitination - genetics; Ubiquitination - physiology
• DOI: 10.1038/s41467-019-12033-8
• ISSN: 2041-1723

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 generate Ripk1 knock-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 in Ripk1 cells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality of Ripk1 mice. Notably, Ripk1 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.