RIPK1 ubiquitination regulates its kinase-independent function in development and inflammation
Abstract
Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cell death and inflammation, with its activation modulated by diverse posttranslational modifications. While ubiquitination of RIPK1 at lysine 376 (K376) has been shown to inhibit apoptosis and necroptosis both in vitro and in vivo, its role in inflammation remains undefined. In this study, we introduced a kinase-dead D138N mutation into Ripk1 K376R/K376R mice. Notably, Ripk1 K376R,D138N/K376R,D138N mice rescued the embryonic lethality observed in Ripk1 K376R/K376R mice, but developed systemic inflammation. Remarkably, this inflammation was significantly alleviated by codeletion of Caspase-1/11 , but not Trif , indicating a critical role for inflammasome activation. Mechanistically, loss of ubiquitination at the K376 residue of RIPK1 promotes kinase activity-dependent cell death, which underlies the lethality of Ripk1 K376R/K376R mice. Importantly, the K376R mutation also drives RIPK1 kinase–independent inflammatory responses by triggering intrinsic NLRP3 inflammasome activation and downstream IL-1β secretion. Furthermore, we found that RIPK1 promotes this process through a RIPK3-dependent mechanism. Consistently, deletion of Ripk3 —but not Mlkl —ameliorated this inflammation, highlighting a necroptosis-independent inflammatory axis. Together, our findings demonstrate that the RIPK1 K376R mutant not only induces kinase activity-dependent cell death during embryogenesis but also promotes kinase-independent, scaffold-driven inflammation in adults via RIPK3-mediated metabolic reprogramming that activates the NLRP3 inflammasome.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Ming Li
Jianling Liu
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Mingyan Xing
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Han Liu
Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR 999077, P. R. China
Lingxia Wang
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiaoxia Wu
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yangjing Ou
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiaoming Zhao
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yangyang Wang
Wuya College of Innovation
YangYang Xie
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hanwen Zhang
Zhuyang Wu
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Jincheng Hao
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hong Li
Yu Li
Haibing Zhang
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences