2. Academic Validation
  3. RIPK1 S213E mutant suppresses RIPK1-dependent cell death by preventing interactions with RIPK3 and CASP8

RIPK1 S213E mutant suppresses RIPK1-dependent cell death by preventing interactions with RIPK3 and CASP8

  • Cell Death Discov. 2025 Jul 25;11(1):345. doi: 10.1038/s41420-025-02647-x.
Ning Nan 1 2 3,  Hong Hu 4 5 6,  Xinxin Zhu 4 5 6,  Jia Liu 4 5 6,  Feiyang Yuan 4 5 6,  Zhijie Li 4 5 6,  Huayi Wang 7 8
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. nanning@shanghaitech.edu.cn.
  • 2 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. nanning@shanghaitech.edu.cn.
  • 3 University of Chinese Academy of Sciences, Beijing, China. nanning@shanghaitech.edu.cn.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 5 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.
  • 6 University of Chinese Academy of Sciences, Beijing, China.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huayi.wang@beigene.com.
  • 8 Beigene, Ltd., Shanghai, China. huayi.wang@beigene.com.
PMID: 40715038 DOI: 10.1038/s41420-025-02647-x
Abstract

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.

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