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

• Published in: Cell death & disease 2022-07, Vol.13 (7), p.653-653, Article 653
• Main Authors: Wu, Jie, Liu, Qinjie, Zhang, Xufei, Tan, Miaomiao, Li, Xuanheng, Liu, Peizhao, Wu, Lei, Jiao, Fan, Lin, Zhaoyu, Wu, Xiuwen, Wang, Xin, Zhao, Yun, Ren, Jianan
• Format: Article
• Language: English
• Subjects: 101/58; 13/21; 42/89; 631/250/1932; 64/60; 692/699/255/1318; 82/51; 82/80; 96/109; 96/47; 96/98; Animals; Antibodies; Binding sites; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Ferroptosis; High-throughput screening; Immune response; Immunity, Innate - genetics; Immunology; Inflammation; Innate immunity; Interferon; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Life Sciences; Localization; Macrophages; Macrophages - metabolism; Mass spectroscopy; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Nuclear Receptor Coactivators - metabolism; Nucleotide sequence; Peripheral blood mononuclear cells; Sepsis; Sepsis - genetics; Transcription Factors - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05115-x

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.