Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex

作者：Sihui Cai, Chenqiu Zhang, Zhen Zhuang, Shengnan Zhang, Ling Ma, Shuai Yang, Tao Zhou, Zheyu Wang, Weihong Xie, Shouheng Jin, Jincun Zhao, Xiangdong Guan, Jianfeng Wu, Jun Cui, Yaoxing Wu · 发表于：Signal Transduction and Targeted Therapy · 年份：2023 · DOI：10.1038/s41392-023-01420-9 · 被引用次数：69 · 研究领域：interferon and immune responses、SARS-CoV-2 and COVID-19 Research、RNA Research and Splicing

Currently, the incidence and fatality rate of SARS-CoV-2 remain continually high worldwide. COVID-19 patients infected with SARS-CoV-2 exhibited decreased type I interferon (IFN-I) signal, along with limited activation of antiviral immune responses as well as enhanced viral infectivity. Dramatic progresses have been made in revealing the multiple strategies employed by SARS-CoV-2 in impairing canonical RNA sensing pathways. However, it remains to be determined about the SARS-CoV-2 antagonism of cGAS-mediated activation of IFN responses during infection. In the current study, we figure out that SARS-CoV-2 infection leads to the accumulation of released mitochondria DNA (mtDNA), which in turn triggers cGAS to activate IFN-I signaling. As countermeasures, SARS-CoV-2 nucleocapsid (N) protein restricts the DNA recognition capacity of cGAS to impair cGAS-induced IFN-I signaling. Mechanically, N protein disrupts the assembly of cGAS with its co-factor G3BP1 by undergoing DNA-induced liquid-liquid phase separation (LLPS), subsequently impairs the double-strand DNA (dsDNA) detection ability of cGAS. Taken together, our findings unravel a novel antagonistic strategy by which SARS-CoV-2 reduces DNA-triggered IFN-I pathway through interfering with cGAS-DNA phase separation.