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Use of Two Dimensional Semi-denaturing Detergent Agarose Gel Electrophoresis to Confirm Size Heterogeneity of Amyloid or Amyloid-like Fibers
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Intercellular propagation of RIPK1/RIPK3 amyloid fibrils

Yeyang Ma1,2, Qiuyuan Zhang1,2, Dekang Li1,2

  • 1University of Chinese Academy of Sciences, Beijing 100049, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 16, 2025
PubMed

Insights

Functional amyloid fibrils of RIPK1 and RIPK3 are released from dying cells and can infect other cells, initiating necroptosis. This study reveals the structural basis for this intercellular spreading and templating mechanism.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The necrosome, composed of RIPK1 and RIPK3, is a crucial amyloid fibril structure driving necroptosis.
  • Necroptosis releases cellular contents, but the fate of RIPK1/RIPK3 fibrils post-necroptosis remains unknown.

Purpose of the Study:

  • To investigate the fate and function of RIPK1/RIPK3 fibrils after necroptotic cell death.
  • To elucidate the structural mechanisms underlying the intercellular spread of necroptosis.

Main Methods:

  • Tracking RIPK1 and RIPK3 coassemblies in necroptotic cells.
  • Cryo-electron microscopy for structural analysis of RIPK1/RIPK3 fibrils.
  • Assessing the ability of released fibrils to infect recipient cells.

Main Results:

  • RIPK1/RIPK3 fibrillar aggregates are released into the medium upon necroptotic cell membrane rupture.
  • These released fibrils can infiltrate recipient cells and seed endogenous necrosome formation.
  • Cryo-EM revealed a common S-shaped conformation in RHIM fibrils, facilitating cross-seeding between RIPK1 and RIPK3.

Conclusions:

  • Functional RIPK1/RIPK3 amyloid fibrils can spread between cells, inducing conformational changes and promoting necroptosis.
  • Structural insights into RIPK1/RIPK3 cross-templating provide a deeper understanding of necroptosis regulation.
Keywords:
RIPK1RIPK3amyloidnecroptosisnecrosome

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