Nan Ning, Hu Hong, Zhu Xinxin, Liu Jia, Yuan Feiyang, Li Zhijie, Wang Huayi
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Cell Death Discov. 2025 Jul 25;11(1):345. doi: 10.1038/s41420-025-02647-x.
RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) is fundamental in regulating cell proliferation, programmed cell death, and inflammation. Within the TNF (tumor necrosis factor) signaling pathway, the kinase activity of RIPK1 is essential for determining cellular fate, promoting either apoptosis or necroptosis. Mutations disrupting RIPK1 kinase activity significantly impact cellular fate decisions, highlighting its importance in the TNF signaling cascade. This study generated and characterized a novel mutation of human RIPK1, S213E that exhibits unique inhibitory properties. Although located in the kinase domain, the S213E mutation disrupts RIPK1 homodimerization and its interactions with downstream effectors, such as RIPK3, without directly suppressing RIPK1 kinase activity. These findings indicate that the S213E mutation converts RIPK1 into a super-autoinhibitory state, effectively isolating it from downstream effectors involved in both apoptosis and necroptosis.
RIPK1（受体相互作用丝氨酸/苏氨酸蛋白激酶1）在调节细胞增殖、程序性细胞死亡和炎症方面至关重要。在TNF（肿瘤坏死因子）信号通路中，RIPK1的激酶活性对于决定细胞命运、促进凋亡或坏死性凋亡至关重要。破坏RIPK1激酶活性的突变会显著影响细胞命运决定，突出了其在TNF信号级联反应中的重要性。本研究产生并鉴定了一种新型的人类RIPK1突变体S213E，它具有独特的抑制特性。尽管位于激酶结构域，但S213E突变破坏了RIPK1的同型二聚化及其与下游效应分子（如RIPK3）的相互作用，而没有直接抑制RIPK1的激酶活性。这些发现表明，S213E突变将RIPK1转变为一种超级自抑制状态，有效地将其与参与凋亡和坏死性凋亡的下游效应分子隔离开来。
