Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling
Jiayi Chen, Zixin Lu, Xiuwen Yang, Yezhen Zhou, Jing Gao, Shihao Zhang, Shan Huang, Jintai Cai, Jianhai Yu, Wei Zhao, Bao Zhang
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has currently infected over 430 million individuals worldwide. With the variant strains of SARS-CoV-2 emerging, a region of high mutation rates in ORF8 was identified during the early pandemic, which resulted in a mutation from leucine (L) to serine (S) at amino acid 84. A typical feature of ORF8 is the immune evasion by suppressing interferon response; however, the mechanisms by which the two variants of ORF8 antagonize the type I interferon (IFN-I) pathway have not yet been clearly investigated. Here, we reported that SARS-CoV-2 ORF8L and ORF8S with no difference inhibit the production of IFN-β, MDA5, RIG-I, ISG15, ISG56, IRF3, and other IFN-related genes induced by poly(I:C). In addition, both ORF8L and ORF8S proteins were found to suppress the nuclear translocation of IRF3. Mechanistically, the SARS-CoV-2 ORF8 protein interacts with HSP90B1, which was later investigated to induce the production of IFN-β and IRF3. Taken together, these results indicate that SARS-CoV-2 ORF8 antagonizes the RIG-I/MDA-5 signaling pathway by targeting HSP90B1, which subsequently exhibits an inhibitory effect on the production of IFN-I. These functions appeared not to be influenced by the genotypes of ORF8L and ORF8S. Our study provides an explanation for the antiviral immune suppression of SARS-CoV-2 and suggests implications for the pathogenic mechanism and treatment of COVID-19.