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Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1

Xue, Yaoyao ; Pan, Lang ; Vlahopoulos, Spiros ; Wang, Ke ; Zheng, Xu ; Radak, Zsolt ; Bacsi, Attila ; Tanner, Lloyd LU ; Brasier, Allan R. and Ba, Xueqing , et al. (2023) In Frontiers in Immunology 14.
Abstract

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1... (More)

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1 significantly augment IFN-λ expression in epithelial cells infected by human respiratory syncytial virus (RSV). Mechanistically, OGG1 bound to 8-oxoGua in proximity to interferon response elements, which inhibits the IRF3/IRF7 and NF-κB/RelA DNA occupancy, while promoting the suppressor NF-κB1/p50-p50 homodimer binding to the IFN-λ2/3 promoter. In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
IFN-λ, innate immune response, IRF, NF-κB, ROS, small airway epithelium
in
Frontiers in Immunology
volume
14
article number
1161160
publisher
Frontiers Media S. A.
external identifiers
  • pmid:37600772
  • scopus:85168388624
ISSN
1664-3224
DOI
10.3389/fimmu.2023.1161160
language
English
LU publication?
yes
id
8dfc4f0e-379b-487b-827e-24e5fc6d23c1
date added to LUP
2023-11-13 14:09:45
date last changed
2024-04-25 05:26:42
@article{8dfc4f0e-379b-487b-827e-24e5fc6d23c1,
  abstract     = {{<p>Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1 significantly augment IFN-λ expression in epithelial cells infected by human respiratory syncytial virus (RSV). Mechanistically, OGG1 bound to 8-oxoGua in proximity to interferon response elements, which inhibits the IRF3/IRF7 and NF-κB/RelA DNA occupancy, while promoting the suppressor NF-κB1/p50-p50 homodimer binding to the IFN-λ2/3 promoter. In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response.</p>}},
  author       = {{Xue, Yaoyao and Pan, Lang and Vlahopoulos, Spiros and Wang, Ke and Zheng, Xu and Radak, Zsolt and Bacsi, Attila and Tanner, Lloyd and Brasier, Allan R. and Ba, Xueqing and Boldogh, Istvan}},
  issn         = {{1664-3224}},
  keywords     = {{IFN-λ; innate immune response; IRF; NF-κB; ROS; small airway epithelium}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2023.1161160}},
  doi          = {{10.3389/fimmu.2023.1161160}},
  volume       = {{14}},
  year         = {{2023}},
}