Journal
SCIENCE
Volume 376, Issue 6593, Pages 609-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abg5251
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Funding
- National Outstanding Youth Science Fund Project of the National Natural Science Foundation [82025021]
- National Natural Science Foundation of China [81930059, 81801888, 81971893]
- key scientific project of Hunan Province [2022SK2056]
- China Postdoctoral Science Foundation [2019M652811]
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The study reveals that ZBP1 plays a crucial role in heatstroke by triggering RIPK3-dependent cell death. Deletion of ZBP1, RIPK3, or both MLKL and caspase-8 reduces circulatory failure, organ injury, and lethality induced by heat stress.
Heatstroke is a heat stress-induced, life-threatening condition associated with circulatory failure and multiple organ dysfunctions. If global warming continues, heatstroke might become a more prominent cause of mortality worldwide, but its pathogenic mechanism is not well understood. We found that Z-DNA binding protein 1 (ZBP1), a Z-nucleic acid receptor, mediated heatstroke by triggering receptor-interacting protein kinase 3 (RIPK3)-dependent cell death. Heat stress increased the expression of ZBP1 through heat shock transcription factor 1 (HSF1) and activated ZBP1 through a mechanism independent of the nucleic acid sensing action. Deletion of ZBP1, RIPK3, or both mixed lineage kinase domain-like (MLKL) and caspase-8 decreased heat stress-induced circulatory failure, organ injury, and lethality. Thus, ZBP1 appears to have a second function that orchestrates host responses to heat stress.
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