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TitleRegulation of STING activation by phosphoinositide and cholesterol.
Journal, issue, pagesNature, Year 2026
Publish dateFeb 4, 2026
AuthorsJie Li / Jay Xiaojun Tan / Zhijian J Chen / Xuewu Zhang / Xiao-Chen Bai /
PubMed AbstractStimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP ...Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS). cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P and PtdIns(4,5)P, 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.
External linksNature / PubMed:41639452
MethodsEM (single particle)
Resolution2.6 - 2.9 Å
Structure data

46694

9dan

EMDB-46694, PDB-9dan:
STING oligomer bound to PI(4,5)P2
Method: EM (single particle) / Resolution: 2.6 Å

46697

9dat

EMDB-46697, PDB-9dat:
STING oligomer bound to PI(3,5)P2
Method: EM (single particle) / Resolution: 2.9 Å

46699

9dav

EMDB-46699, PDB-9dav:
STING oligomer bound to cGAMP and STG2 in the presence of PI4P
Method: EM (single particle) / Resolution: 2.8 Å

46700

9daw

EMDB-46700, PDB-9daw:
STING oligomer bound to cGAMP, C53 and PI(3,5)P2
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-Y6H:
4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid

PDB-1bbg:
RAGWEED POLLEN ALLERGEN FROM AMBROSIA TRIFIDA V, NMR, MINIMIZED AVERAGE STRUCTURE

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-1SY:
cGAMP

PDB-1bbh:
ATOMIC STRUCTURE OF A CYTOCHROME C' WITH AN UNUSUAL LIGAND-CONTROLLED DIMER DISSOCIATION AT 1.8 ANGSTROMS RESOLUTION

ChemComp-9IM:
1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN/ACTIVATOR / STING / lipid / oligomerization / SIGNALING PROTEIN / SIGNALING PROTEIN-ACTIVATOR complex / oligomer / PI(3 / 5)P2

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