Regulation of STING activation by phosphoinositide and cholesterol

  • Nature. 2026 Apr;652(8109):499-507. doi: 10.1038/s41586-025-10076-0.
Jie Li  1 ,  Jay Xiaojun Tan  2  3  4  5 ,  Zhijian J Chen  2  3  6 ,  Xuewu Zhang  7  8 ,  Xiao-Chen Bai  9  10
Affiliations
  • 1. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3. Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4. Aging Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 5. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 6. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 8. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 9. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 10. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
PMID: 41639452 DOI: 10.1038/s41586-025-10076-0
Abstract

Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway1. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS)2-5. cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation6-11. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and Cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear12-17. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 and PtdIns(4,5)P2, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with Cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and Cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific Lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.