SARS‐CoV‐2 ORF10 antagonizes STING‐dependent interferon activation and autophagy

• Published in: Journal of medical virology Vol. 94; no. 11; pp. 5174 - 5188
• Main Authors: Han, Lulu, Zheng, Yi, Deng, Jian, Nan, Mei‐Ling, Xiao, Yang, Zhuang, Meng‐Wei, Zhang, Jing, Wang, Wei, Gao, Chengjiang, Wang, Pei‐Hui
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2022; John Wiley and Sons Inc
• Subjects: Autophagy; Coronaviruses; COVID-19; Cytokine storm; Cytokines; Endoplasmic reticulum; Golgi apparatus; Humans; IFN; Immune response; Immune system; Immunity, Innate; Infections; Inflammation; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon Type I - genetics; Interferons; Membrane Proteins - genetics; Membrane Proteins - metabolism; Micronuclei; Nucleotidyltransferases - genetics; Oligomerization; Open Reading Frames; ORF10; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Proteins; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Signaling; STING; Syncytia; Translocation; Viral diseases; Viral infections; Viral Proteins - metabolism; Virology; Viruses; COVID-19; IFN; STING; SARS-CoV-2; autophagy; ORF10
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.27965

A characteristic feature of COVID‐19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is the dysregulated immune response with impaired type I and III interferon (IFN) expression and an overwhelming inflammatory cytokine storm. RIG‐I‐like receptors (RLRs) and cGAS–STING signaling pathways are responsible for sensing viral infection and inducing IFN production to combat invading viruses. Multiple proteins of SARS‐CoV‐2 have been reported to modulate the RLR signaling pathways to achieve immune evasion. Although SARS‐CoV‐2 infection also activates the cGAS–STING signaling by stimulating micronuclei formation during the process of syncytia, whether SARS‐CoV‐2 modulates the cGAS–STING pathway requires further investigation. Here, we screened 29 SARS‐CoV‐2‐encoded viral proteins to explore the viral proteins that affect the cGAS–STING signaling pathway and found that SARS‐CoV‐2 open reading frame 10 (ORF10) targets STING to antagonize IFN activation. Overexpression of ORF10 inhibits cGAS–STING‐induced interferon regulatory factor 3 phosphorylation, translocation, and subsequent IFN induction. Mechanistically, ORF10 interacts with STING, attenuates the STING–TBK1 association, and impairs STING oligomerization and aggregation and STING‐mediated autophagy; ORF10 also prevents the endoplasmic reticulum (ER)‐to‐Golgi trafficking of STING by anchoring STING in the ER. Taken together, these findings suggest that SARS‐CoV‐2 ORF10 impairs the cGAS–STING signaling by blocking the translocation of STING and the interaction between STING and TBK1 to antagonize innate antiviral immunity.