Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense
Open accessAbstract
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.
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Prior studies indicate that AhR controls the type I interferon response.
“given studies suggesting regulation of type I IFN response by AhR (41).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [41]
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References 57 · Cited by 251
Research works printed but not linked: 1
- Ed summary: The aryl hydrocarbon receptor (AHR) has well-described roles in the differentiation of T cells; however, less is known about its function in innate immunity. Takaoka and colleagues demonstrate how an AHR-dependent pathway reins in production of type I interferon. hepatic growth and development. Proc. Natl. Acad. Sci. USA 93, 6731-6736 (1996).
- Authors
- Yamada, T., Horimoto, H., Kameyama, T., Hayakawa, S., Yamato, H., Dazai, M., Takada, A., Kida, H., Bott, D., Zhou, A. C., Hutin, D., Watts, T. H., Asaka, M., Matthews, J., & Takaoka, A.
- Affiliations
- Hokkaido University (JP)
- University of Toronto (CA)
- Health Sciences University of Hokkaido (JP)
- University of Oslo (NO)
- Corresponding author
- Takaoka, Akinori
- ORCID
- Venue
- Nature Immunology
- Published
- 2016-04-18
- Volume
- 17
- Issue
- 6
- Pages
- 687-694
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2341631860
- Cited by
- 251
- References
- 57
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 26 · 2023: 35 · 2022: 24 · 2021: 40 · 2020: 20 · 2019: 14 · 2018: 21 · 2017: 15 · 2016: 3
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- Funders
- Akiyama Life Science Foundation
- Kato Memorial Bioscience Foundation
- Yasuda Memorial Medical Foundation
- Waksman Foundation of Japan
- Canadian Institutes of Health Research (125919_1, 496441)
- Japan Society for the Promotion of Science (24390110, 25713032, 15H01249, 25253030)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- aryl hydrocarbon receptor, type I interferon, interferon-beta, antiviral innate immunity, TIPARP, ADP-ribosylation, TBK1, viral replication, AhR signaling, transcription factor regulation
- MeSH terms
- Animals, Gene Expression Regulation, HeLa Cells, Humans, Immunity, Innate, Interferon Type I, Mice, Inbred C57BL, Poly(ADP-ribose) Polymerases, Virus Diseases, Virus Replication, Signal Transduction, Transcriptional Activation, Receptors, Aryl Hydrocarbon, Mice, Knockout, RNA, Small Interfering, Mice, HEK293 Cells
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