Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1
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. Unexpected...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161160/full |
| _version_ | 1797754589115580416 |
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| author | Yaoyao Xue Yaoyao Xue Lang Pan Spiros Vlahopoulos Ke Wang Ke Wang Xu Zheng Xu Zheng Zsolt Radak Attila Bacsi Lloyd Tanner Allan R. Brasier Xueqing Ba Istvan Boldogh |
| author_facet | Yaoyao Xue Yaoyao Xue Lang Pan Spiros Vlahopoulos Ke Wang Ke Wang Xu Zheng Xu Zheng Zsolt Radak Attila Bacsi Lloyd Tanner Allan R. Brasier Xueqing Ba Istvan Boldogh |
| author_sort | Yaoyao Xue |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T17:35:33Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T17:35:33Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-672e0898900943f687352329b70e5da32023-08-04T11:55:06ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.11611601161160Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1Yaoyao Xue0Yaoyao Xue1Lang Pan2Spiros Vlahopoulos3Ke Wang4Ke Wang5Xu Zheng6Xu Zheng7Zsolt Radak8Attila Bacsi9Lloyd Tanner10Allan R. Brasier11Xueqing Ba12Istvan Boldogh13Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesKey Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Science, Northeast Normal University, Changchun, ChinaDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesHoremeio Research Laboratory, First Department of Pediatrics, National and Kapodistrian, University of Athens, Athens, GreeceDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesKey Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Science, Northeast Normal University, Changchun, ChinaDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesKey Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Science, Northeast Normal University, Changchun, ChinaResearch Institute of Molecular Exercise Science, University of Sport Science, Budapest, HungaryDepartment of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, HungaryRespiratory Medicine, Allergology & Palliative Medicine, Lund University and Skåne University Hospital, Lund, SwedenDepartment of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United StatesKey Laboratory of Molecular Epigenetics of Ministry of Education, School of Life Science, Northeast Normal University, Changchun, ChinaDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesInterferons (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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161160/fullROSNF-κBIRFIFN-λsmall airway epitheliuminnate immune response |
| spellingShingle | Yaoyao Xue Yaoyao Xue Lang Pan Spiros Vlahopoulos Ke Wang Ke Wang Xu Zheng Xu Zheng Zsolt Radak Attila Bacsi Lloyd Tanner Allan R. Brasier Xueqing Ba Istvan Boldogh Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 Frontiers in Immunology ROS NF-κB IRF IFN-λ small airway epithelium innate immune response |
| title | Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 |
| title_full | Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 |
| title_fullStr | Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 |
| title_full_unstemmed | Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 |
| title_short | Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1 |
| title_sort | epigenetic control of type iii interferon expression by 8 oxoguanine and its reader 8 oxoguanine dna glycosylase1 |
| topic | ROS NF-κB IRF IFN-λ small airway epithelium innate immune response |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161160/full |
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