NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway
COMMUNICATIONS BIOLOGY(2022)
摘要
Emerging evidence suggests that pyroptosis is involved in sepsis. However, the role of neutrophil pyroptosis in sepsis and the mechanisms remains elusive. We find that N-acetyltransferase 10 (NAT10), an acetyltransferase responsible for the N 4 -acetylation of Cytidine (ac 4 C) in mRNA, is significantly downregulated in neutrophils from septic mice. Neutrophil-specific over-expression of NAT10 improves the survival and ameliorates lung injury in septic mice by inhibiting neutrophil pyroptosis. Notably, UNC-52-like kinase 1 (ULK1) is identified as the target of NAT10 in neutrophils. The decreased expression of NAT10 resultes in the decay of ULK1 transcripts and therefore the reduced expression of ULK1. As a regulator of STING phosphorylation, the loss of ULK1 enhances the activation of STING-IRF3 signaling and subsequently the elevated pyroptosis-inducing NLRP3 inflammasome in neutrophils. While over-expression of NAT10 restrains pyroptosis in neutrophils as well as septic lethality in mice by reversing the ULK1-STING-NLRP3 axis. The decreased expression of NAT10 are also observed in sepsis patients and its correlation with clinical severity is found. Collectively, our findings disclose that NAT10 is a negative regulator of neutrophil pyroptosis and its downregulation contributes to the progress of sepsis by exacerbating pyroptosis via the ULK1-STING-NLRP3 axis, therefore revealing a potential therapeutic target for sepsis.
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关键词
neutrophil pyroptosis,sepsis,ulk1 rna,nat10
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