STING protein (Stimulator of Interferon Genes, encoded by STING1/TMEM173) is a 42 kDa transmembrane adaptor protein that resides on the endoplasmic reticulum and functions as the central signaling hub of the cGAS-STING innate immune pathway. Upon binding the cyclic dinucleotide 2'3'-cGAMP produced by cGAS in response to cytosolic DNA, STING undergoes conformational activation, traffics to the Golgi, and triggers TBK1-dependent type I interferon and NF-κB-dependent inflammatory cytokine production. Chronic STING activation in brain microglia and astrocytes is a major contributor to neuroinflammation in Alzheimer's disease, Parkinson's disease, and aging.
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| Protein Name | Stimulator of Interferon Genes |
| Gene | [STING1 (TMEM173)](/genes/sting1) |
| UniProt ID | [Q86WV6](https://www.uniprot.org/uniprot/Q86WV6) |
| PDB IDs | [6NT5](https://www.rcsb.org/structure/6NT5), [4KSY](https://www.rcsb.org/structure/4KSY), [4LOH](https://www.rcsb.org/structure/4LOH) |
| Molecular Weight | 42.2 kDa |
| Subcellular Localization | Endoplasmic reticulum, ER-Golgi intermediate compartment, Golgi apparatus |
| Protein Family | STING family (TMEM173) |
| Associated Diseases | [AD](/diseases/alzheimers-disease), [PD](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), SAVI |
STING is a homodimeric integral membrane protein with four transmembrane helices per monomer:
- Transmembrane region (residues 1-154): Four TM helices anchor STING in the ER membrane and form the dimerization interface
- Connector helix (residues 155-180): Links the TM domain to the cytoplasmic domain
- Ligand-binding domain (LBD) (residues 181-340): V-shaped dimer that binds cGAMP in the central pocket
- C-terminal tail (CTT) (residues 341-379): Contains the TBK1-binding motif (pLxIS) and the IRF3 recruitment site
In the resting state, the STING LBD dimer adopts an "open" conformation. cGAMP binding induces a dramatic 180° rotation of the LBD, creating a "closed" conformation that:
- Buries cGAMP in a deep pocket at the dimer interface
- Reorients the CTT to expose the TBK1-binding pLxIS motif
- Promotes STING oligomerization into higher-order complexes required for signaling
- Palmitoylation (Cys88, Cys91): Required for STING clustering in Golgi and signaling; targeted by inhibitors H-151 and C-178
- Phosphorylation (Ser366): By TBK1, creates the IRF3 docking site
- K63-linked ubiquitination: By TRIM56 and TRIM32, promotes STING activation
- K48-linked ubiquitination: By RNF5 and TRIM30α, targets STING for proteasomal degradation (negative regulation)
STING serves as the essential adaptor linking cytosolic DNA detection to interferon and inflammatory responses:
- cGAMP binding activates STING, which then traffics from ER → ERGIC → Golgi
- At the Golgi, STING recruits TBK1, which phosphorylates both STING (Ser366) and IRF3
- Activated IRF3 dimerizes and enters the nucleus to induce IFN-β and interferon-stimulated genes (ISGs)
- STING also activates NF-κB through mechanisms involving IKK and TRAF6
STING independently activates autophagy through a non-canonical pathway:
- STING-induced ERGIC membranes serve as platforms for LC3 lipidation
- This STING-autophagy axis helps degrade invading pathogens and cytosolic DNA
- Impaired STING-autophagy may contribute to cytosolic DNA accumulation in aging
- Microglia are the primary STING-expressing cells in the CNS
- Astrocytic STING contributes to reactive astrogliosis and A1 polarization
- Neuronal STING expression is low but upregulated by DNA damage stress
- STING signaling at the blood-brain barrier regulates immune cell infiltration
- Tau pathology disrupts the nuclear envelope, releasing chromatin fragments that activate neuronal cGAS-STING
- PQBP1 acts as a co-sensor that enhances cGAS recognition of tau-induced cytosolic DNA
- STING-driven IFN-β production in microglia promotes complement-mediated synapse elimination
- STING knockout rescues cognitive deficits and reduces neuroinflammation in PS19 tauopathy mice
- Amyloid-beta-induced mitochondrial damage releases mtDNA, activating cGAS-STING in microglia
- PINK1/Parkin-mediated mitophagy normally prevents mtDNA escape; loss-of-function mutations cause STING hyperactivation
- Prkn−/−;Pink1−/− mice develop STING-dependent systemic and CNS inflammation that is fully rescued by crossing to Sting1−/−
- α-Synuclein aggregation fragments mitochondria, releasing mtDNA into the cytosol
- LRRK2 G2019S enhances STING pathway activity in macrophages and microglia
- TDP-43 nuclear loss derepresses retrotransposons (LINE-1), producing cytosolic DNA that activates cGAS-STING
- C9orf72 haploinsufficiency impairs STING degradation through reduced autophagy, prolonging signaling
- STING pathway genes are upregulated in ALS patient spinal cord microglia
- Age-related accumulation of cytosolic mtDNA and retrotransposon DNA chronically activates cGAS-STING
- STING-driven type I IFN signaling promotes cellular senescence and the senescence-associated secretory phenotype (SASP)
- Genetic STING ablation in aged mice reduces brain inflammation and improves cognition
- H-151: Covalent inhibitor targeting Cys91 palmitoylation site; blocks STING oligomerization; efficacious in neurodegeneration models
- C-178 / C-176: Covalent STING inhibitors blocking ER-to-Golgi trafficking
- SN-011: Competitive cGAMP-binding antagonist
- Astin C: Natural product inhibitor of STING signaling
- RU.521: Potent cGAS catalytic inhibitor; prevents cGAMP production
- G150: cGAS inhibitor effective in mouse inflammation models
- CNS penetrance remains a key challenge for STING-targeting therapeutics
- Complete STING blockade may impair antiviral immunity; partial inhibition strategies are preferred
- Combination with anti-amyloid or anti-tau therapies may provide synergistic benefit