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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Virology
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1525648

Frk positively regulates innate antiviral immunity by phosphorylating TBK1

Provisionally accepted
Xiaomei Zhang Xiaomei Zhang 1Ying You Ying You 2Tingrong Xiong Tingrong Xiong 3,4Xiaokai Zhang Xiaokai Zhang 3Haibo Wang Haibo Wang 3Jinxia Geng Jinxia Geng 3Miao Wang Miao Wang 3Yanyan Xu Yanyan Xu 3Shanshan Gao Shanshan Gao 3,4Xiaoyan Wu Xiaoyan Wu 3Yue Zheng Yue Zheng 3Xianhua Wen Xianhua Wen 3Haoyu Yang Haoyu Yang 3Yu Wang Yu Wang 3Xiaohua Wen Xiaohua Wen 5Congcong Zhao Congcong Zhao 3*
  • 1 Xinqiao Hospital, Shapingba, Chongqing, China
  • 2 Southwest Hospital, Army Medical University, Chongqing, China
  • 3 Army Medical University, Chongqing, China
  • 4 Chongqing University, Chongqing, China
  • 5 Department of Ophthalmology, The 980th Hospital of the Chinese PLA Joint Logistics Support Force, Shijiazhuang, Hebei Province, China

The final, formatted version of the article will be published soon.

    Type I interferons (IFN-I) are crucial for the initial defense against viral infections. TBK1 is a key regulator in the production of IFN-I, but the regulatory mechanisms controlling its activation have not yet been fully elucidated. Here we found that Fynrelated kinase (Frk), a non-receptor tyrosine kinase, 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. Utilizing both in vivo and in vitro viral infection assays, we demonstrated that IFN-β mediated by Frk inhibited VSV or HSV-1 replication and mitigated lung lesions. Our findings indicate that Frk acts as a key regulator of TBK1 to strengthen antiviral immunity and was a promising target for the development of anti-virus drugs.

    Keywords: Macrophages, FRK, TBK1, Phosphorylation, IFN-I

    Received: 10 Nov 2024; Accepted: 24 Jan 2025.

    Copyright: © 2025 Zhang, You, Xiong, Zhang, Wang, Geng, Wang, Xu, Gao, Wu, Zheng, Wen, Yang, Wang, Wen and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Congcong Zhao, Army Medical University, Chongqing, China

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