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  3. Mosaic composition of RIP1-RIP3 signalling hub and its role in regulating cell death

Mosaic composition of RIP1-RIP3 signalling hub and its role in regulating cell death

  • Nat Cell Biol. 2022 Apr;24(4):471-482. doi: 10.1038/s41556-022-00854-7.
Xin Chen 1,  Rongfeng Zhu 2,  Jinjin Zhong 3,  Yongfa Ying 3,  Wenxin Wang 2,  Yating Cao 2,  Hanyi Cai 2,  Xiang Li 3,  Jianwei Shuai 3 4,  Jiahuai Han 5 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China. xchen@xmu.edu.cn.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.
  • 3 Department of Physics and Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen, China.
  • 4 National Institute for Data Science in Health and Medicine, Xiamen, China.
  • 5 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China. jhan@xmu.edu.cn.
  • 6 National Institute for Data Science in Health and Medicine, Xiamen, China. jhan@xmu.edu.cn.
  • 7 Research Unit of Cellular Stress of CAMS, Cancer Research Center of Xiamen University, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. jhan@xmu.edu.cn.
PMID: 35256774 DOI: 10.1038/s41556-022-00854-7
Abstract

RIP1 and RIP3, cell death mediators, form fibrous amyloids. How RIP1/RIP3 amyloidal oligomers assemble functional necrosomes and control cell death is largely unknown. Here we use super-resolution microscopy to directly visualize cellular necrosomes as mosaics of RIP1 and RIP3 oligomers. The small (initial) mosaic complexes are round, and the large mosaics are in a rod shape. RIP3 oligomers with sizes of tetramer or above are the domains in mosaics that allow MLKL, recruited by phosphorylated RIP3, to oligomerize for Necroptosis. Unexpectedly, RIP1 autophosphorylation not only controls the ordered oligomerization of RIP1 but also is required for RIP1-initiated RIP3 homo-oligomerization in correct organization, which is indispensable for the formation of functional rod-shaped mosaics. Similarly, Apoptosis initiated by enzymatically defective RIP3 requires the formation of rod-shaped mosaics of RIP3 and RIP1 oligomers. The revealing of nanoscale architecture of necrosomes here innovates our understanding of the structural and organizational basis of this signalling hub in cell death.

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