STING1 (Stimulator of Interferon Genes 1, also known as TMEM173 or MITA) encodes the STING protein, a critical adaptor in the cGAS-STING innate immune signaling pathway. STING detects cytosolic double-stranded DNA (dsDNA) — a danger-associated molecular pattern released from damaged mitochondria, stressed nuclei, and dying cells — and triggers type I interferon and inflammatory cytokine production. In the central nervous system, aberrant cGAS-STING activation in microglia and astrocytes is increasingly recognized as a driver of chronic neuroinflammation in Alzheimer's disease, Parkinson's disease, ALS, and age-related neurodegeneration.
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| Full Name | Stimulator of Interferon Genes 1 |
| Gene Symbol | STING1 (TMEM173) |
| Chromosomal Location | 5q31.2 |
| NCBI Gene ID | [340061](https://www.ncbi.nlm.nih.gov/gene/340061) |
| Ensembl ID | [ENSG00000184584](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184584) |
| UniProt ID | [Q86WV6](https://www.uniprot.org/uniprot/Q86WV6) |
| Protein | [STING Protein](/proteins/sting1-protein) |
| Associated Diseases | [AD](/diseases/alzheimers-disease), [PD](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/frontotemporal-dementia), SAVI |
STING1 encodes the central signaling hub of the cytosolic DNA sensing pathway:
- DNA sensing: cGAS (cyclic GMP-AMP synthase) binds cytosolic dsDNA from any source — mitochondrial, nuclear, microbial, or retrotransposon-derived
- Second messenger synthesis: Activated cGAS catalyzes the synthesis of 2'3'-cyclic GMP-AMP (cGAMP), a cyclic dinucleotide second messenger
- STING activation: cGAMP binds to the STING dimer on the endoplasmic reticulum membrane, inducing a conformational change
- STING trafficking: Activated STING traffics from the ER to the Golgi via COPII vesicles
- Kinase recruitment: At the Golgi, STING recruits and activates TBK1 (TANK-binding kinase 1)
- Transcription factor activation: TBK1 phosphorylates IRF3 and activates NF-κB
- Gene induction: Phospho-IRF3 translocates to the nucleus and induces type I interferons (IFN-α, IFN-β); NF-κB induces pro-inflammatory cytokines (TNF-α, IL-6, IL-1β)
- Autophagic degradation: STING is ultimately degraded through autophagy to terminate signaling
- Mitochondrial DNA (mtDNA): Released through mitochondrial permeability transition pore (mPTP) opening, BAX/BAK pores, and impaired mitophagy
- Nuclear DNA: Released during DNA damage, chromatin remodeling defects, and micronuclei formation
- Retrotransposon DNA: LINE-1 and Alu element reverse transcription products accumulate with aging and epigenetic derepression
- Extracellular DNA: Released from dying neurons and taken up by phagocytic glia
cGAS-STING is activated at multiple stages of AD pathology:
- Tau pathology induces nuclear envelope disruption and cytosolic chromatin release, activating cGAS-STING in neurons and microglia
- Amyloid-beta-induced mitochondrial damage releases mtDNA into the cytosol
- Microglial STING activation promotes senescence-associated secretory phenotype (SASP)
- Genetic variants near STING1 show nominal association with AD risk in GWAS
- STING knockout in tauopathy mice (PS19) reduces neuroinflammation, brain atrophy, and p-tau levels
- IFN-β signaling downstream of STING drives complement activation and synapse loss
- PINK1/Parkin deficiency impairs mitophagy, leading to mtDNA accumulation in the cytosol
- Pink1−/− and Prkn−/− mice show STING-dependent systemic inflammation; crossing to Sting1−/− rescues the inflammatory phenotype
- α-Synuclein aggregation causes mitochondrial fragmentation and mtDNA release
- LRRK2 mutations enhance STING-dependent IFN-β production in macrophages and microglia
- Dopaminergic neurons in the substantia nigra show elevated cGAS and STING expression in PD postmortem tissue
- TDP-43 loss of nuclear function leads to retrotransposon derepression and cytosolic DNA accumulation
- C9orf72 repeat expansions produce DPR aggregates that damage mitochondria and trigger mtDNA release
- SOD1 mutant motor neurons show enhanced cGAS-STING activation
- STING inhibition extends survival in SOD1-G93A mice
Normal aging is associated with progressive cGAS-STING activation due to:
- Accumulation of cytosolic mtDNA from age-related mitochondrial dysfunction
- Derepression of retrotransposable elements (particularly LINE-1)
- Increased DNA damage and micronuclei formation
- This "sterile inflammation" or inflammaging contributes to age-related neurodegeneration
Gain-of-function mutations in STING1 (e.g., V155M, N154S) cause SAVI, a severe autoinflammatory disease with constitutive type I IFN production. Although primarily a systemic vasculopathy, SAVI patients can develop CNS inflammation including basal ganglia calcification.
- Microglia: High STING expression; primary CNS responders to cytosolic DNA
- Astrocytes: Moderate expression; astrocytic STING signaling promotes A1 reactive phenotype
- Neurons: Low basal expression but upregulated under stress; neuronal STING may contribute to cell-autonomous inflammatory signaling
- Oligodendrocytes: Low expression
- Endothelial cells: Moderate expression; relevant for blood-brain barrier inflammation
- H-151: Covalent small molecule STING inhibitor; blocks palmitoylation required for STING clustering and signaling; efficacious in tauopathy and PD mouse models
- C-178 and C-176: Covalent STING inhibitors that block trafficking from ER to Golgi
- SN-011: Non-covalent STING antagonist that competes with cGAMP binding
- Astin C: Natural product STING inhibitor from Aster tataricus
- cGAS inhibitors: RU.521, G150 block the DNA sensor upstream of STING
- DNase delivery: Enhanced degradation of cytosolic DNA to reduce cGAS activation
Several STING inhibitors are in early clinical development for autoimmune conditions. Repurposing for neurodegeneration requires demonstration of CNS penetrance and sustained target engagement.