2. Academic Validation
  3. NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway

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

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.

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