Frk positively regulates innate antiviral immunity by phosphorylating TBK1

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...

Full description

Saved in:
Bibliographic Details
Main Authors: Xiaomei Zhang, Ying You, Tingrong Xiong, Xiaokai Zhang, Haibo Wang, Jinxia Geng, Miao Wang, Yanyan Xu, Shanshan Gao, Xiaoyan Wu, Yue Zheng, Xianhua Wen, Haoyu Yang, Yu Wang, Xiaohua Wen, Congcong Zhao
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-02-01
Series:Frontiers in Microbiology
Subjects:
macrophages
Frk
TBK1
phosphorylation
IFN-I
Online Access:https://www.frontiersin.org/articles/10.3389/fmicb.2025.1525648/full
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1664-302X

Similar Items