Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense

Nat Immunol. 2016 Jun;17(6):687-94. doi: 10.1038/ni.3422. Epub 2016 Apr 18.

Abstract

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood. Here we demonstrate that constitutive AHR signaling negatively regulates the type I interferon (IFN-I) response during infection with various types of virus. Virus-induced IFN-β production was enhanced in AHR-deficient cells and mice and resulted in restricted viral replication. We found that AHR upregulates expression of the ADP-ribosylase TIPARP, which in turn causes downregulation of the IFN-I response. Mechanistically, TIPARP interacted with the kinase TBK1 and suppressed its activity by ADP-ribosylation. Thus, this study reveals the physiological importance of endogenous activation of AHR signaling in shaping the IFN-I-mediated innate response and, further, suggests that the AHR-TIPARP axis is a potential therapeutic target for enhancing antiviral responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Interferon Type I / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • RNA, Small Interfering / genetics
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction
  • Transcriptional Activation
  • Virus Diseases / immunology*
  • Virus Replication

Substances

  • Interferon Type I
  • RNA, Small Interfering
  • Receptors, Aryl Hydrocarbon
  • 2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase, mouse
  • Poly(ADP-ribose) Polymerases