Influenza virus NS1- C/EBPβ gene regulatory complex inhibits RIG-I transcription

Antiviral Res. 2020 Apr;176:104747. doi: 10.1016/j.antiviral.2020.104747. Epub 2020 Feb 21.

Abstract

Influenza virus non-structural protein 1 (NS1) counteracts host antiviral innate immune responses by inhibiting Retinoic acid inducible gene-I (RIG-I) activation. However, whether NS1 also specifically regulates RIG-I transcription is unknown. Here, we identify a CCAAT/Enhancer Binding Protein beta (C/EBPβ) binding site in the RIG-I promoter as a repressor element, and show that NS1 promotes C/EBPβ phosphorylation and its recruitment to the RIG-I promoter as a C/EBPβ/NS1 complex. C/EBPβ overexpression and siRNA knockdown in human lung epithelial cells resulted in suppression and activation of RIG-I expression respectively, implying a negative regulatory role of C/EBPβ. Further, C/EBPβ phosphorylation, its interaction with NS1 and occupancy at the RIG-I promoter was associated with RIG-I transcriptional inhibition. These findings provide an important insight into the molecular mechanism by which influenza NS1 commandeers RIG-I transcriptional regulation and suppresses host antiviral responses.

Keywords: C/EBPβ; Influenza; NS1; RIG-I; Transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta
  • DEAD Box Protein 58 / genetics*
  • DEAD Box Protein 58 / immunology
  • Gene Expression Regulation*
  • Host Microbial Interactions / genetics
  • Humans
  • Immunity, Innate*
  • Influenza A virus / genetics*
  • Influenza A virus / immunology
  • Influenza, Human / virology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Receptors, Immunologic
  • Transcription, Genetic
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / immunology*

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • INS1 protein, influenza virus
  • Receptors, Immunologic
  • Viral Nonstructural Proteins
  • DDX58 protein, human
  • DEAD Box Protein 58