NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

  • Commun Biol. 2022 Sep 6;5(1):916. doi: 10.1038/s42003-022-03868-x.
Hao Zhang   #  1  2 ,  Zhaoyuan Chen   #  1  2 ,  Ji'an Zhou   #  3 ,  Jiahui Gu  1  2 ,  Han Wu  1  2 ,  Yi Jiang  1  2 ,  Shenjia Gao  1  2 ,  Yun Liao  4 ,  Rulin Shen  5 ,  Changhong Miao  6  7 ,  Wankun Chen  8  9  10
Affiliations
  • 1. Department of Anesthesiology, Zhongshan Hospital, Fudan University; Cancer Center, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
  • 2. Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, China.
  • 3. Department of Respiratory and Critical Care Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
  • 4. Shanghai Medical College of Fudan University, Shanghai, China.
  • 5. Shanghai Laboratory Animal Research Center, 201203, Shanghai, China. [email protected].
  • 6. Department of Anesthesiology, Zhongshan Hospital, Fudan University; Cancer Center, Zhongshan Hospital, Fudan University, 200032, Shanghai, China. [email protected].
  • 7. Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, China. [email protected].
  • 8. Department of Anesthesiology, Zhongshan Hospital, Fudan University; Cancer Center, Zhongshan Hospital, Fudan University, 200032, Shanghai, China. [email protected].
  • 9. Shanghai Key laboratory of Perioperative Stress and Protection, Shanghai, China. [email protected].
  • 10. Fudan Zhangjiang Institute, Shanghai, 201203, China. [email protected].
  • # Contributed equally.
PMID: 36068299 DOI: 10.1038/s42003-022-03868-x
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.

Products