2. Academic Validation
  3. The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages

The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages

  • Cell Death Dis. 2022 Jul 28;13(7):653. doi: 10.1038/s41419-022-05115-x.
Jie Wu  # 1,  Qinjie Liu  # 2,  Xufei Zhang  # 3,  Miaomiao Tan  # 4 5 6,  Xuanheng Li 2,  Peizhao Liu 2,  Lei Wu 2,  Fan Jiao 1,  Zhaoyu Lin 7,  Xiuwen Wu 8 9 10,  Xin Wang 11 12 13,  Yun Zhao 14,  Jianan Ren 15 16 17
Affiliations

Affiliations

  • 1 Department of General Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 2 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
  • 3 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 4 Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
  • 5 Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, Kowloon Tong, City University of Hong Kong, Hong Kong, SAR, China.
  • 6 Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
  • 7 MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
  • 8 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. [email protected].
  • 9 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 10 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, China. [email protected].
  • 11 Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China. [email protected].
  • 12 Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, Kowloon Tong, City University of Hong Kong, Hong Kong, SAR, China. [email protected].
  • 13 Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China. [email protected].
  • 14 Department of General Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. [email protected].
  • 15 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. [email protected].
  • 16 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 17 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 35902564 DOI: 10.1038/s41419-022-05115-x
Abstract

The discovery of STING-related innate immunity has recently provided a deep mechanistic understanding of immunopathy. While the detrimental effects of STING during sepsis had been well documented, the exact mechanism by which STING causes lethal sepsis remains obscure. Through single-cell RNA sequence, genetic approaches, and mass spectrometry, we demonstrate that STING promotes sepsis-induced multiple organ injury by inducing macrophage Ferroptosis in a cGAS- and interferon-independent manner. Mechanistically, Q237, E316, and S322 in the CBD domain of STING are critical binding sites for the interaction with the coiled-coil domain of NCOA4. Their interaction not only triggers ferritinophagy-mediated Ferroptosis, but also maintains the stability of STING dimers leading to enhanced inflammatory response, and reduces the nuclear localization of NCOA4, which impairs the transcription factor coregulator function of NCOA4. Meanwhile, we identified HET0016 by high throughput screening, a selective 20-HETE synthase inhibitor, decreased STING-induced Ferroptosis in peripheral blood mononuclear cells from patients with sepsis and mortality in septic mice model. Our findings uncover a novel mechanism by which the interaction between STING and NCOA4 regulates innate immune response and Ferroptosis, which can be reversed by HET0016, providing mechanistic and promising targets insights into sepsis.

Figures
Products
Inhibitors & Agonists