Frk positively regulates innate antiviral immunity by phosphorylating TBK1
Type I interferons (IFN-I) are crucial for the initial defense against viral infections. TBK1 serves as a key regulator in the production of IFN-I, with its phosphorylation being essential for the regulation of its activity. However, the regulatory mechanisms governing its activation remain incomple...
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| Format: | Article |
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1525648/full |
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| author | Xiaomei Zhang Ying You Tingrong Xiong Tingrong Xiong Xiaokai Zhang Haibo Wang Jinxia Geng Miao Wang Yanyan Xu Shanshan Gao Shanshan Gao Xiaoyan Wu Yue Zheng Xianhua Wen Haoyu Yang Yu Wang Yu Wang Xiaohua Wen Congcong Zhao |
| author_facet | Xiaomei Zhang Ying You Tingrong Xiong Tingrong Xiong Xiaokai Zhang Haibo Wang Jinxia Geng Miao Wang Yanyan Xu Shanshan Gao Shanshan Gao Xiaoyan Wu Yue Zheng Xianhua Wen Haoyu Yang Yu Wang Yu Wang Xiaohua Wen Congcong Zhao |
| author_sort | Xiaomei Zhang |
| collection | DOAJ |
| description | Type I interferons (IFN-I) are crucial for the initial defense against viral infections. TBK1 serves as a key regulator in the production of IFN-I, with its phosphorylation being essential for the regulation of its activity. However, the regulatory mechanisms governing its activation remain incompletely elucidated. In this study, we validated the function of Fyn-related kinase (Frk) in the antiviral innate immune response and identified the direct target molecule of Frk in the IFN-β signaling pathway. Furthermore, we elucidated the mechanism by which Frk phosphorylates TBK1 during infection and the role of Frk in IFN-β production. We discovered that Frk enhances the activation of the IFN-I production pathway by targeting TBK1. Mechanistically, Frk promotes the K63 ubiquitination of TBK1 and subsequent activation of the transcription factor IRF3 by phosphorylating TBK1 at tyrosine residues 174 and 179, thereby enhancing the production of IFN-β in macrophages. Employing both in vivo and in vitro viral infection assays, we demonstrated that IFN-β mediated by Frk inhibits the replication of VSV or HSV-1 and alleviates lung lesions. Our findings indicate that Frk functions as a key regulator of TBK1 to strengthen antiviral immunity and represents a promising target for the development of antiviral drugs. |
| format | Article |
| id | doaj-art-e9a37e3b59654542a9c5616ca8e965d7 |
| institution | Kabale University |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj-art-e9a37e3b59654542a9c5616ca8e965d72025-02-12T07:26:07ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-02-011610.3389/fmicb.2025.15256481525648Frk positively regulates innate antiviral immunity by phosphorylating TBK1Xiaomei Zhang0Ying You1Tingrong Xiong2Tingrong Xiong3Xiaokai Zhang4Haibo Wang5Jinxia Geng6Miao Wang7Yanyan Xu8Shanshan Gao9Shanshan Gao10Xiaoyan Wu11Yue Zheng12Xianhua Wen13Haoyu Yang14Yu Wang15Yu Wang16Xiaohua Wen17Congcong Zhao18Department of Medical Engineering, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, ChinaClinical Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaChongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Basic Courses, Non Commissioned Officer School, Third Military Medical University, Shijiazhuang, ChinaDepartment of Basic Courses, Non Commissioned Officer School, Third Military Medical University, Shijiazhuang, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaChongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaDepartment of Basic Courses, Non Commissioned Officer School, Third Military Medical University, Shijiazhuang, ChinaDepartment of Health Medicine, The 980th Hospital of People’s Liberation Army Joint Logistics Support Forces, Shijiazhuang, ChinaDepartment of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, ChinaType I interferons (IFN-I) are crucial for the initial defense against viral infections. TBK1 serves as a key regulator in the production of IFN-I, with its phosphorylation being essential for the regulation of its activity. However, the regulatory mechanisms governing its activation remain incompletely elucidated. In this study, we validated the function of Fyn-related kinase (Frk) in the antiviral innate immune response and identified the direct target molecule of Frk in the IFN-β signaling pathway. Furthermore, we elucidated the mechanism by which Frk phosphorylates TBK1 during infection and the role of Frk in IFN-β production. We discovered that Frk enhances the activation of the IFN-I production pathway by targeting TBK1. Mechanistically, Frk promotes the K63 ubiquitination of TBK1 and subsequent activation of the transcription factor IRF3 by phosphorylating TBK1 at tyrosine residues 174 and 179, thereby enhancing the production of IFN-β in macrophages. Employing both in vivo and in vitro viral infection assays, we demonstrated that IFN-β mediated by Frk inhibits the replication of VSV or HSV-1 and alleviates lung lesions. Our findings indicate that Frk functions as a key regulator of TBK1 to strengthen antiviral immunity and represents a promising target for the development of antiviral drugs.https://www.frontiersin.org/articles/10.3389/fmicb.2025.1525648/fullmacrophagesFrkTBK1phosphorylationIFN-I |
| spellingShingle | Xiaomei Zhang Ying You Tingrong Xiong Tingrong Xiong Xiaokai Zhang Haibo Wang Jinxia Geng Miao Wang Yanyan Xu Shanshan Gao Shanshan Gao Xiaoyan Wu Yue Zheng Xianhua Wen Haoyu Yang Yu Wang Yu Wang Xiaohua Wen Congcong Zhao Frk positively regulates innate antiviral immunity by phosphorylating TBK1 Frontiers in Microbiology macrophages Frk TBK1 phosphorylation IFN-I |
| title | Frk positively regulates innate antiviral immunity by phosphorylating TBK1 |
| title_full | Frk positively regulates innate antiviral immunity by phosphorylating TBK1 |
| title_fullStr | Frk positively regulates innate antiviral immunity by phosphorylating TBK1 |
| title_full_unstemmed | Frk positively regulates innate antiviral immunity by phosphorylating TBK1 |
| title_short | Frk positively regulates innate antiviral immunity by phosphorylating TBK1 |
| title_sort | frk positively regulates innate antiviral immunity by phosphorylating tbk1 |
| topic | macrophages Frk TBK1 phosphorylation IFN-I |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1525648/full |
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