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

  • Cell Discov. 2025 Mar 18;11(1):23. doi: 10.1038/s41421-024-00763-z.
Jinrui Wang  #  1 ,  Shenghui Niu  #  1 ,  Xiao Hu  1 ,  Tianxing Li  1 ,  Shengduo Liu  2 ,  Yingfeng Tu  1 ,  Zehua Shang  1 ,  Lin Zhao  1 ,  Pinglong Xu  2 ,  Jingwen Lin  1 ,  Lu Chen  1 ,  Daniel D Billadeau  3 ,  Da Jia  4  5
Affiliations
  • 1. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
  • 2. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3. Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
  • 4. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 5. Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • # Contributed equally.
PMID: 40097395 DOI: 10.1038/s41421-024-00763-z
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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