A new study in PNAS, achieved by a joined research team led by Profs. YUAN Junying and LIU Cong at IRCBC, SIOC, CAS, shows that amyloid fibrils formed by necroptosis mediators RIPK1 and RIPK3 don’t just form within dying cells – they can also escape the cell and trigger necroptotic death in neighboring cells. Using super-resolution microscopy, the researchers observed that as cells undergo necroptosis, RIPK1 and RIPK3 proteins co-assemble into fibrous, rod-like structures inside the cell. Within hours of necroptotic stimulus, these small protein puncta elongated into fibril-like assemblies in the cytoplasm, confirming that necroptosis involves an amyloid-like polymerization of its core signaling proteins. As necroptotic cells eventually rupture, the internal RIPK1/RIPK3 fibrils are released into the surrounding medium. The team found that these extracellular fibrils can spontaneously enter nearby cells and seed the aggregation of the cells’ own RIPK1 and RIPK3, thereby initiating the necroptosis program in previously unaffected cells. In essence, the fibrils act as transmissible “necroptotic seeds.” Even fibrils reconstituted in vitro from the purified RIPK1 and RIPK3 RHIM (RIP homotypic interaction motif) domains were highly potent at inducing cell death when introduced into cells. This demonstrates that the amyloid form of these proteins is itself a functional signal capable of propagating cell death across cells. To understand how one cell’s death signal fibrils trigger another’s, the researchers solved the molecular structure of the fibrils using cryo-electron microscopy. Remarkably, RIPK1 and RIPK3 fibrils were found to share a nearly identical S-shaped β-sheet fold. This common conformation explains their cross-seeding ability: a fibril of RIPK1 can template the monomers of RIPK3 to assemble into a new fibril of the same architecture (and vice versa). In other words, the two proteins’ fibrils are structurally compatible, allowing a heterologous amyloid to form. Furthermore, when the team introduced mutations that disrupted the S-shaped folding of the RIPK3 RHIM region, the mutant RIPK3 could no longer be recruited into fibrils by RIPK1 seeds, and necroptotic cell death was effectively suppressed. This finding confirms that the specific amyloid fold is critical for the intercellular transmission of the death signal. This study reveals a previously unrecognized mode of cell-to-cell communication in programmed necrosis – essentially a prion-like mechanism by which dying cells can induce death in others. Unlike the well-known amyloid aggregates in Alzheimer’s or Parkinson’s disease, which pathologically spread neurodegeneration, the RIPK1/RIPK3 fibrils serve a functional signaling role in cell death. The necroptotic amyloids propagate an inflammatory form of cell death rather than a neurodegenerative pathology. Notably, the authors suggest that these necroptosis-related fibrils could even act as “seeds” that potentially initiate pathological amyloid formation in disease contexts. In broader terms, the discovery highlights an amyloid-based intercellular signal propagation mechanism in human cells, demonstrating that cells can harness prion-like protein aggregation not just for causing disease, but as a deliberate means to amplify a death signal in certain biological scenarios.
YUAN Junying Ph.D.Professor Interdisciplinary Research Center on Biology and Chemistry (IRCBC) Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Haike Road 100 Shanghai 201204 China Email: junying_yuan@sioc.ac.cn
LIU Cong Ph.D.Professor Interdisciplinary Research Center on Biology and Chemistry (IRCBC) Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Haike Road 345 Shanghai 201204 China Email: liulab@sioc.ac.cn |
