Pseudorabies virus glycoprotein gE suppresses interferon-β production via CREB-binding protein degradation

Virus Res. 2021 Jan 2;291:198220. doi: 10.1016/j.virusres.2020.198220. Epub 2020 Nov 2.

Abstract

Cyclic GMP-AMP synthase (cGAS) is a main sensor used to detect microbial DNA in the cytoplasm, which subsequently induces the production of interferon (IFN) via the cGAS/STING/IRF3 signaling pathway, leading to an antiviral response. However, some viruses have evolved multiple strategies to escape this process. Pseudorabies virus (PRV) is a double-stranded DNA virus belonging to the Alphaherpesvirinae subfamily, which can cause serious damage to the porcine industry. Many herpesvirus components have been reported to counteract IFN production, whereas little is known of PRV. In the present study, we found that PRV glycoprotein E (gE) was involved in counteracting cGAS/STING-mediated IFN production. Ectopic expression of gE decreased cGAS/STING-mediated IFN-β promoter activity and the level of mRNA expression. Moreover, gE targeted at or downstream of IRF3 was found to inhibit IFN-β production. However, gE did not affect the phosphorylation, dimerization and nuclear translocation of IRF3. Furthermore, gE is located on the nuclear membrane and could subsequently degrade CREB-binding protein (CBP). MG132, a proteasome inhibitor, decreased CBP degradation and restored the IFN-β production induced by gE. Finally, gE-deleted PRV induced a higher level of IFN-β production and reduced CBP degradation compared to wild-type PRV. Together, these results demonstrate that PRV gE can inhibit cGAS/STING-mediated IFN-β production by degrading CBP to interrupt the enhanced assembly of IRF3 and CBP.

Keywords: CBP; DNA-sensing; Interferon; PRV; gE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism*
  • Chlorocebus aethiops
  • HEK293 Cells
  • Herpesvirus 1, Suid / chemistry
  • Herpesvirus 1, Suid / genetics
  • Herpesvirus 1, Suid / immunology*
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / antagonists & inhibitors*
  • Interferon-beta / immunology
  • Phosphorylation
  • Signal Transduction / immunology
  • Swine
  • Vero Cells
  • Viral Envelope Proteins / genetics*
  • Viral Envelope Proteins / immunology*

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Viral Envelope Proteins
  • glycoprotein E, Suid herpesvirus 1
  • Interferon-beta
  • CREB-Binding Protein