Journal Club: Z-DNA binding protein 1 promotes heatstroke-induced cell death

SCIENCE • 5 May 2022 • Vol 376, Issue 6593 • pp. 609-615

Understanding heat-induced necrosis

Z-DNA binding protein 1 (ZBP1), a sensor for Z–nucleic acids, is implicated in necrosis caused by heat stress in the worm Caenorhabditis elegans. Yuan et al. examined the roles of proteins that regulate necrosis in worms undergoing heat stroke. The protein kinase receptor-interacting protein kinase 3 (RIPK3) leads to activation of mixed lineage kinase domain-like (MLKL) and Caspase-8, and all were required for heat-induced death. ZBP1 is a RIPK3 and necrosis activator and it appeared to contribute to heat-induced necrosis in the worms. This response did not require the nucleic acid–sensing domain of ZBP1. Transcription of ZBP1 was enhanced by heat shock transcription factor 1 (HSF1).

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.