IFN regulatory factor-1 bypasses IFN-mediated antiviral effects through viperin gene induction

J Immunol. 2010 May 1;184(9):5179-85. doi: 10.4049/jimmunol.0902264. Epub 2010 Mar 22.

Abstract

Viperin is an antiviral protein whose expression is highly upregulated during viral infections via IFN-dependent and/or IFN-independent pathways. We examined the molecular alterations induced by the transcriptional activator IFN regulatory factor (IRF)-1 and found viperin to be among the group of IRF-1 regulated genes. From these data, it was not possible to distinguish genes that are primary targets of IRF-1 and those that are targets of IRF-1-induced proteins, like IFN-beta. In this study, we show that IRF-1 directly binds to the murine viperin promoter to the two proximal IRF elements and thereby induces viperin expression. Infection studies with embryonal fibroblasts from different gene knock-out mice demonstrate that IRF-1 is essential, whereas the type I IFN system is dispensable for vesicular stomatitis virus induced viperin gene transcription. Further, IRF-1, but not IFN type I, mediates the induction of viperin transcription after IFN-gamma treatment. In contrast, IRF-1 is not required for IFN-independent viperin induction by Newcastle disease virus infection and by infection with a vesicular stomatitis virus mutant that is unable to block IFN expression and secretion. We conclude that the IRF-1 mediated type I IFN independent mechanism of enhanced viperin expression provides a redundant mechanism to protect cells from viral infections. This mechanism becomes important when viruses evade innate immunity by antagonizing the induction and function of the IFN system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / antagonists & inhibitors
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Interferon Regulatory Factor-1 / deficiency
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / physiology*
  • Interferon Type I / antagonists & inhibitors
  • Interferon Type I / physiology*
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Promoter Regions, Genetic / immunology
  • Proteins / genetics*
  • Proteins / metabolism
  • Signal Transduction / immunology
  • Transcriptional Activation / immunology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology
  • Vesicular Stomatitis / immunology
  • Vesicular Stomatitis / prevention & control
  • Vesicular stomatitis Indiana virus / immunology*
  • Virus Replication / immunology

Substances

  • Antiviral Agents
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • Irf1 protein, mouse
  • Proteins
  • vig1 protein, mouse