炎症におけるRIPK1ユビキチン化の新規機能を解明（RIPK1 Ubiquitination Regulates Kinase-independent Function in Inflammation）

2026-04-13 中国科学院（CAS）

＜関連情報＞

• https://english.cas.cn/newsroom/research-news/202604/t20260409_1155576.shtml
• https://www.pnas.org/doi/10.1073/pnas.2520356123

RIPK1のユビキチン化は、発生と炎症におけるキナーゼ非依存的な機能を調節する RIPK1 ubiquitination regulates its kinase-independent function in development and inflammation

Ming Li, Jianling Liu, Mingyan Xing, +12 , and Haibing Zhang
Proceedings of the National Academy of Sciences  Published:April 7, 2026
DOI:https://doi.org/10.1073/pnas.2520356123

Significance

Receptor-interacting protein kinase 1 (RIPK1) is a central regulator of apoptosis, necroptosis, and inflammation, with distinct functions determined by its scaffold role and kinase activity. Posttranslational modifications of RIPK1-particularly ubiquitination-play critical roles in controlling its activation. Here, we show that loss of ubiquitination at lysine 376 not only causes embryonic lethality through RIPK1 kinase-dependent cell death but also drives systemic inflammation in adult mice through a kinase-independent, scaffold-dependent mechanism. This inflammatory response is mediated by RIPK3-dependent inflammasome activation and subsequent IL-1β secretion, with additional contributions from TNFR1-induced cell death. These findings reveal previously unrecognized dual roles of RIPK1 in development and inflammatory regulation and provide a conceptual framework for understanding the pathogenesis of RIPK1-associated inflammatory diseases.

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.