Format

Send to

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

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

Author information

1
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
2
Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
3
Molecular Medical Biochemistry Unit, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
4
Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
5
Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan.
6
Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
7
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
8
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
9
Health Sciences University of Hokkaido, Toubetu, Japan.
10
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

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.

PMID:
27089381
DOI:
10.1038/ni.3422
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center