2. Academic Validation
  3. A chemical agonist and the Golgi-resident lipid PI4P activate STING by inducing transmembrane helix rearrangement

A chemical agonist and the Golgi-resident lipid PI4P activate STING by inducing transmembrane helix rearrangement

  • Immunity. 2025 Dec 5:S1074-7613(25)00506-0. doi: 10.1016/j.immuni.2025.11.004.
Jing Han 1,  Shuhao Zhang 2,  Yanfei Hou 1,  Yi Wang 1,  Zhengyin Zhang 1,  Jiaming Yang 1,  Yifang Xu 1,  Zexu Peng 3,  Hang Yin 4,  Kehong Chen 5,  Xiangyu Liu 6,  Conggang Zhang 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China; SXMU-Tsinghua, Taiyuan, China.
  • 2 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 3 Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 4 School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  • 5 Department of Nephrology, Daping Hospital, Army Medical University, Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, Chongqing, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. Electronic address: [email protected].
  • 7 School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China; Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China; SXMU-Tsinghua, Taiyuan, China. Electronic address: [email protected].
PMID: 41352342 DOI: 10.1016/j.immuni.2025.11.004
Abstract

The Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.

Keywords

STING agonist; antiviral and antitumor immunity; cGAS-STING pathway; innate immunity; phospholipid PI4P.

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