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NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway.
- Source :
-
Communications Biology . 9/6/2022, Vol. 5 Issue 1, p1-13. 13p. - Publication Year :
- 2022
-
Abstract
- 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 N4-acetylation of Cytidine (ac4C) 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. The enzyme N-acetyltransferase 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 pathway. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 5
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Communications Biology
- Publication Type :
- Academic Journal
- Accession number :
- 158935769
- Full Text :
- https://doi.org/10.1038/s42003-022-03868-x