STING1 Gene
Overview
Pathway Diagram
Mermaid diagram (expand to render)
STING1 (Stimulator of Interferon Genes 1, also known as TMEM173 or MITA) encodes the STING protein, a critical adaptor in the [cGAS](/genes/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](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) is increasingly recognized as a driver of chronic neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), and age-related neurodegeneration.
<div class="infobox infobox-gene"> [@sliter2018]
<div class="infobox-header">STING1</div> [@xie2023]
<table> [@jin2021]
<tr><td class="infobox-label">Full Name</td><td>Stimulator of Interferon Genes 1</td></tr> [@mccauley2020]
<tr><td class="infobox-label">Gene Symbol</td><td>STING1 (TMEM173)</td></tr> [@paul2021]
<tr><td class="infobox-label">Chromosomal Location</td><td>5q31.2</td></tr> [@ablasser2019]
<tr><td class="infobox-label">NCBI Gene ID</td><td>[340061](https://www.ncbi.nlm.nih.gov/gene/340061)</td></tr> [@gulen2023]
<tr><td class="infobox-label">Ensembl ID</td><td>[ENSG00000184584](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184584)</td></tr>
<tr><td class="infobox-label">UniProt ID</td><td>[Q86WV6](https://www.uniprot.org/uniprot/Q86WV6)</td></tr>
<tr><td class="infobox-label">Protein</td><td>[STING Protein](/proteins/sting1-protein)</td></tr>
<tr><td class="infobox-label">Associated Diseases</td><td>[AD](/diseases/alzheimers-disease), [PD](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/frontotemporal-dementia), SAVI</td></tr>
</table>
</div>
Function
The cGAS-STING Pathway
STING1 encodes the central signaling hub of the cytosolic DNA sensing pathway:
DNA sensing: [cGAS](/genes/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](/genes/tbk1) (TANK-binding kinase 1)
Transcription factor activation: TBK1 phosphorylates [IRF3](/genes/irf3) and activates [NF-κB](/entities/nf-kb)
Gene induction: Phospho-IRF3 translocates to the nucleus and induces type I interferons (IFN-α, [IFN-β](/genes/ifnb1)); NF-κB induces pro-inflammatory cytokines ([TNF-α](/genes/tnf), [IL-6](/genes/il6), [IL-1β](/genes/il1b))
Autophagic degradation: STING is ultimately degraded through [autophagy](/entities/autophagy) to terminate signalingSources of Cytosolic DNA in Neurodegeneration
- Mitochondrial DNA (mtDNA): Released through mitochondrial permeability transition pore (mPTP) opening, [BAX](/genes/bax)/[BAK](/genes/bak1) 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](/entities/neurons) and taken up by phagocytic glia
Disease Associations
Alzheimer's Disease
cGAS-STING is activated at multiple stages of AD pathology:
- [Tau](/proteins/tau) pathology induces nuclear envelope disruption and cytosolic chromatin release, activating cGAS-STING in neurons and [microglia](/cell-types/microglia-neuroinflammation)
- [Amyloid-beta](/proteins/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](/biomarkers/p-tau) levels
- IFN-β signaling downstream of STING drives complement activation and synapse loss
Parkinson's Disease
- [PINK1](/genes/pink1)/[Parkin](/genes/prkn) 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](/proteins/alpha-synuclein) aggregation causes mitochondrial fragmentation and mtDNA release
- [LRRK2](/genes/lrrk2) mutations enhance STING-dependent IFN-β production in macrophages and microglia
- Dopaminergic neurons in the [substantia nigra](/brain-regions/substantia-nigra) show elevated cGAS and STING expression in PD postmortem tissue
Amyotrophic Lateral Sclerosis / Frontotemporal Dementia
- [TDP-43](/genes/tardbp) loss of nuclear function leads to retrotransposon derepression and cytosolic DNA accumulation
- [C9orf72](/genes/c9orf72) repeat expansions produce DPR aggregates that damage mitochondria and trigger mtDNA release
- [SOD1](/entities/sod1) mutant motor neurons show enhanced cGAS-STING activation
- STING inhibition extends survival in SOD1-G93A mice
Aging
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
STING-Associated Vasculopathy (SAVI)
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.
Expression
- Microglia: High STING expression; primary CNS responders to cytosolic DNA
- [Astrocytes](/entities/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](/mechanisms/blood-brain-barrier) inflammation
Therapeutic Targeting
STING Inhibitors
- 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
Upstream Targets
- cGAS inhibitors: RU.521, G150 block the DNA sensor upstream of STING
- DNase delivery: Enhanced degradation of cytosolic DNA to reduce cGAS activation
Clinical Development
Several STING inhibitors are in early clinical development for autoimmune conditions. Repurposing for neurodegeneration requires demonstration of CNS penetrance and sustained target engagement.
See Also
- [cGAS](/genes/cgas) — cytosolic DNA sensor upstream of STING
- [TBK1](/genes/tbk1) — kinase downstream of STING
- [IRF3](/genes/irf3) — transcription factor activated by STING
- [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
External Links
- [NCBI Gene: STING1](https://www.ncbi.nlm.nih.gov/gene/340061)
- [UniProt: Q86WV6](https://www.uniprot.org/uniprot/Q86WV6)
- [GeneCards: STING1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=STING1)
- [OMIM: TMEM173](https://www.omim.org/entry/612374)
- [Allen Brain Atlas: TMEM173](https://human.brain-map.org/microarray/search/show?search_term=TMEM173)
References
[Decout A et al., The cGAS-STING pathway as a therapeutic target in inflammatory diseases (2021) (2021)](https://doi.org/10.1038/s41577-021-00524-z)
[Sliter DA et al., Parkin and PINK1 mitigate STING-induced inflammation (2018) (2018)](https://doi.org/10.1038/s41586-018-0448-9)
[Xie X et al., Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5×FAD mice (2023) (2023)](https://doi.org/10.1038/s43587-023-00372-x)
[Jin M et al., Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation (2021) (2021)](https://doi.org/10.1038/s41593-021-00911-y)
[McCauley ME et al., C9orf72 in myeloid cells suppresses STING-induced inflammation (2020) (2020)](https://doi.org/10.1038/s41586-020-2625-x)
[Paul BD et al., Signaling by cGAS-STING in neurodegeneration, neuroinflammation, and aging (2021) (2021)](https://doi.org/10.1016/j.tins.2020.10.008)
[Unknown, Ablasser A & Chen ZJ, cGAS in action: expanding roles in immunity and inflammation (2019) (2019)](https://doi.org/10.1126/science.aat8657)
[Gulen MF et al., cGAS-STING drives ageing-related inflammation and neurodegeneration (2023) (2023)](https://doi.org/10.1038/s41586-023-06373-1)From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
- [Senescent Cell Mitochondrial DNA Release](/hypothesis/h-1a34778f) — <span style="color:#ffd54f;font-weight:600">0.54</span> · Target: CGAS/STING1/DNASE2
Pathway Diagram
The following diagram shows the key molecular relationships involving STING1 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)