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Trans-Golgi network tethering factors regulate TBK1 trafficking and promote the STING-IFN-I pathway

Wang, Jinrui, Niu, Shenghui, Hu, Xiao, Li, Tianxing, Liu, Shengduo, Tu, Yingfeng, Shang, Zehua, Zhao, Lin, Xu, Pinglong, Lin, Jingwen, Chen, Lu, Billadeau, Daniel D., Jia, Da·2025·Cell Discovery
DOI 10.1038/s41421-024-00763-zPMC PMC11914254
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Abstract

The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-κB signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.

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Metadata

Authors
Wang, J., Niu, S., Hu, X., Li, T., Liu, S., Tu, Y., Shang, Z., Zhao, L., Xu, P., Lin, J., Chen, L., Billadeau, D. D., & Jia, D.
ORCID
Venue
Cell Discovery
Publisher
Springer Science and Business Media LLC
Published
2025-03-18
Volume
11
Issue
1
ISSN
2056-5968
DOI
10.1038/s41421-024-00763-z
PMC
PMC11914254
Cited by
30
References
8
Language
en
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