Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling

Front Cell Infect Microbiol. 2022 May 23:12:899546. doi: 10.3389/fcimb.2022.899546. eCollection 2022.

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.

Keywords: HSP90B1; IRF3; ORF8 protein; SARS-CoV-2; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / virology
  • Humans
  • Immune Evasion
  • Interferon Type I* / metabolism
  • Interferon-beta / genetics
  • Membrane Glycoproteins* / metabolism
  • SARS-CoV-2
  • Signal Transduction
  • Viral Proteins* / metabolism

Substances

  • Interferon Type I
  • Membrane Glycoproteins
  • ORF8 protein, SARS-CoV-2
  • Viral Proteins
  • endoplasmin
  • Interferon-beta