2025-09-18 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/chem/202509/t20250924_1055286.shtml
- https://www.pnas.org/doi/10.1073/pnas.2507028122
RIPK1/RIPK3アミロイド線維の細胞間伝播 Intercellular propagation of RIPK1/RIPK3 amyloid fibrils
Yeyang Ma, Qiuyuan Zhang, Dekang Li, +7 , and Cong Liu
Proceedings of the National Academy of Sciences Published:September 16, 2025
DOI:https://doi.org/10.1073/pnas.2507028122
Significance
Necroptosis, a form of programmed cell death, has been implicated in mediating diverse neurodegenerative diseases. Propagation of amyloid fibrils has been recognized as an important mechanism underlying neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This study identifies the ability of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 functional amyloid fibrils released by necroptotic cells to infiltrate neighboring cells, seeding the endogenous necrosome assembly and inducing protein conformation changes in recipient cells. Our findings highlight an amyloid-based mechanism underlying intercellular signal propagation during necroptosis, potentially providing seeds to initiate the formation of amyloid fibrils in relevant neurodegenerative diseases.
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.
