Z-DNA binding protein 1 promotes heatstroke-induced cell death
Fangfang Yuan, Jizhen Cai, Jianfeng Wu, Yiting Tang, Kai Zhao, Fang Liang, Fanglin Li, Xinyu Yang, Zhihui He, Timothy R. Billiar, Haichao Wang, Lei Su, Ben Lü
Abstract
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.