The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication

Nat Commun. 2019 Jan 22;10(1):377. doi: 10.1038/s41467-019-08299-7.

Abstract

The circadian clock regulates immune responses to microbes and affects pathogen replication, but the underlying molecular mechanisms are not well understood. Here we demonstrate that the circadian components BMAL1 and REV-ERBα influence several steps in the hepatitis C virus (HCV) life cycle, including particle entry into hepatocytes and RNA genome replication. Genetic knock out of Bmal1 and over-expression or activation of REV-ERB with synthetic agonists inhibits the replication of HCV and the related flaviruses dengue and Zika via perturbation of lipid signaling pathways. This study highlights a role for the circadian clock component REV-ERBα in regulating flavivirus replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / immunology
  • ARNTL Transcription Factors / pharmacology
  • Cell Line
  • Circadian Clocks / genetics*
  • Circadian Clocks / immunology
  • DNA Replication
  • Dengue
  • Dengue Virus / drug effects
  • Dengue Virus / genetics
  • Flavivirus / drug effects
  • Flavivirus / genetics*
  • Flavivirus / metabolism
  • Flavivirus / pathogenicity
  • Gene Expression Regulation / genetics
  • Genes, Essential / genetics
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepacivirus / metabolism
  • Hepatitis C
  • Hepatocytes / immunology
  • Hepatocytes / virology
  • Humans
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics*
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / immunology
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / pharmacology
  • Proteomics
  • RNA, Messenger / metabolism
  • Virus Internalization / drug effects
  • Virus Replication / drug effects*
  • Zika Virus / drug effects
  • Zika Virus / genetics
  • Zika Virus Infection

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • RNA, Messenger