2. Academic Validation
  3. Intercellular propagation of RIPK1/RIPK3 amyloid fibrils

Intercellular propagation of RIPK1/RIPK3 amyloid fibrils

  • Proc Natl Acad Sci U S A. 2025 Sep 23;122(38):e2507028122. doi: 10.1073/pnas.2507028122.
Yeyang Ma # 1 2,  Qiuyuan Zhang # 1 2,  Dekang Li 1 2,  Kun Zhao 1 2,  Zefei Li 1 2,  Yuan Liu 3 4,  Chu Wang 3 4,  Bo Sun 5,  Dan Li 6 7,  Junying Yuan 2 8,  Cong Liu 2 8 9 10
Affiliations

Affiliations

  • 1 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 3 Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 4 Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
  • 7 Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 8 Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China.
  • 9 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 10 Shanghai Academy of Natural Sciences, Fudan University, Shanghai 200433, China.
  • # Contributed equally.
PMID: 40956882 DOI: 10.1073/pnas.2507028122
Abstract

The canonical necrosome formed by receptor-interacting protein kinase 1 (RIPK1) and RIPK3 is a functional amyloid fibril structure critical to intracellularly drive Necroptosis. Since Necroptosis leads to the release of intracellular content, the fate of RIPK1/RIPK3 fibrils after necroptotic cell death has not been investigated. Here, we tracked RIPK1 and RIPK3 coassemblies and found that these fibrillar aggregates could be released into the culture medium after the membrane rupture in necroptotic cells. Interestingly, these RIPK1/RIPK3 fibrils were capable of infiltrating recipient cells and acting as seeds for the nucleation and formation of the endogenous necrosome. Cryo electron microscopy structural analysis unveiled a distinctive S-shaped conformation common to RHIM fibrils of RIPK1 and RIPK3, which can facilitate the cross-seeding of RIPK3 by RIPK1 or RIPK1/RIPK3 fibrils. Our findings suggest the ability of functional RIPK1/RIPK3 amyloid fibrils in intercellular spreading to induce protein conformation change in recipient cells and provide structural insights into the mechanism of RIPK1 and RIPK3 cross-templating to drive Necroptosis.

Keywords

RIPK1; RIPK3; amyloid; necroptosis; necrosome.

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