STING1

Stimulator of interferon genes protein (STING1/TMEM173) is a polytopic membrane protein of the endoplasmic reticulum and the central signalling adaptor of the cytosolic DNA-sensing pathway. Four transmembrane helices anchor it in the ER bilayer and support a cytosolic ligand-binding and signalling domain that forms an obligate dimer. STING1 is the receptor for 2'3'-cyclic GMP-AMP, the second messenger made by cGAS on detection of cytosolic DNA, and it also binds bacterial cyclic dinucleotides such as cyclic di-GMP directly, making it a sensor as well as an adaptor. Ligand binding closes the ligand-binding domain and rotates it relative to the transmembrane domain, driving side-by-side packing of dimers into tetramers and higher-order oligomers. Oligomerisation licenses COPII-dependent exit from the ER to the ER-Golgi intermediate compartment and the Golgi, where TBK1 is recruited and phosphorylates the STING1 C-terminal tail; phosphorylated STING1 then presents a docking surface for IRF3, which TBK1 phosphorylates to induce type I interferons. From post-Golgi endolysosomal compartments STING1 additionally activates NF-kappaB, a branch that can operate independently of interferon signalling, before being degraded in lysosomes. Oligomerisation and ER exit require membrane lipids as well as cGAMP: phosphatidylinositol 3,5-bisphosphate, made by PIKFYVE bound constitutively to STING1, together with cholesterol occupies a groove at the interface between adjacent dimers and acts as a molecular glue; phosphatidylinositol 4,5-bisphosphate binds the same site in vitro. Residue R71, which contacts the lipid 5-phosphate, is part of the common hypofunctional HAQ allele of human STING1. Independently of its adaptor role, the STING1 transmembrane domain conducts protons and deacidifies the Golgi, and this channel activity drives a separable output branch comprising non-canonical LC3B and GABARAP lipidation, inflammasome activation, and TFEB/TFE3-dependent lysosome biogenesis. Autophagy induction is independent of TBK1 and of interferon induction and is the evolutionarily older function of the pathway. Gain-of-function alleles cause the autoinflammatory disease SAVI, and chronic activation of the pathway contributes to senescence, age-related inflammation and neurodegeneration.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

• cgas_sting_pathway_activation via STING-Associated Vasculopathy with Onset in Infancy