STING Protein

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STING Protein

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STING Protein

Overview

STING protein (Stimulator of Interferon Genes, encoded by [STING1/TMEM173](/genes/sting1)) is a 42 kDa transmembrane adaptor protein that resides on the endoplasmic reticulum and functions as the central signaling hub of the [cGAS](/genes/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](/genes/tbk1)-dependent type I interferon and [NF-κB](/entities/nf-kb)-dependent inflammatory cytokine production. Chronic STING activation in brain [microglia](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) is a major contributor to neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and aging.

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STING Protein

Overview

STING protein (Stimulator of Interferon Genes, encoded by [STING1/TMEM173](/genes/sting1)) is a 42 kDa transmembrane adaptor protein that resides on the endoplasmic reticulum and functions as the central signaling hub of the [cGAS](/genes/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](/genes/tbk1)-dependent type I interferon and [NF-κB](/entities/nf-kb)-dependent inflammatory cytokine production. Chronic STING activation in brain [microglia](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) is a major contributor to neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and aging.

<div class="infobox infobox-protein"> [@sliter2018]
<div class="infobox-header">STING Protein</div> [@gulen2023]
<table> [@jin2021]
<tr><td class="infobox-label">Protein Name</td><td>Stimulator of Interferon Genes</td></tr> [@ablasser2019]
<tr><td class="infobox-label">Gene</td><td>[STING1 (TMEM173)](/genes/sting1)</td></tr> [@shang2019]
<tr><td class="infobox-label">UniProt ID</td><td>[Q86WV6](https://www.uniprot.org/uniprot/Q86WV6)</td></tr> [@mccauley2020]
<tr><td class="infobox-label">PDB IDs</td><td>[6NT5](https://www.rcsb.org/structure/6NT5), [4KSY](https://www.rcsb.org/structure/4KSY), [4LOH](https://www.rcsb.org/structure/4LOH)</td></tr>
<tr><td class="infobox-label">Molecular Weight</td><td>42.2 kDa</td></tr>
<tr><td class="infobox-label">Subcellular Localization</td><td>Endoplasmic reticulum, ER-Golgi intermediate compartment, Golgi apparatus</td></tr>
<tr><td class="infobox-label">Protein Family</td><td>STING family (TMEM173)</td></tr>
<tr><td class="infobox-label">Associated Diseases</td><td>[AD](/diseases/alzheimers-disease), [PD](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), SAVI</td></tr>
</table>
</div>

Structure

Topology

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](/genes/irf3) recruitment site

Conformational Activation

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

Post-Translational Modifications

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)

Normal Function

Innate Immune Sensing

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](/proteins/ikk-protein) and TRAF6

Autophagy Induction

STING independently activates [autophagy](/entities/autophagy) through a non-canonical pathway:

STING-induced ERGIC membranes serve as platforms for [LC3](/genes/map1lc3b) lipidation
This STING-autophagy axis helps degrade invading pathogens and cytosolic DNA
Impaired STING-autophagy may contribute to cytosolic DNA accumulation in aging

STING in the Brain

[Microglia](/cell-types/microglia-neuroinflammation) 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](/mechanisms/blood-brain-barrier) regulates immune cell infiltration

Role in Disease

Alzheimer's Disease

[Tau](/proteins/tau) pathology disrupts the nuclear envelope, releasing chromatin fragments that activate neuronal cGAS-STING
[PQBP1](/genes/pqbp1) acts as a co-sensor that enhances cGAS recognition of [tau](/proteins/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](/proteins/amyloid-beta)-induced mitochondrial damage releases mtDNA, activating cGAS-STING in microglia

Parkinson's Disease

[PINK1](/proteins/pink1-protein)/[Parkin](/proteins/parkin-protein)-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](/proteins/alpha-synuclein) aggregation fragments mitochondria, releasing mtDNA into the cytosol
[LRRK2](/proteins/lrrk2-protein) G2019S enhances [STING pathway](/entities/sting-pathway) activity in macrophages and microglia

ALS/FTD

[TDP-43](/proteins/tdp-43-protein) nuclear loss derepresses retrotransposons (LINE-1), producing cytosolic DNA that activates cGAS-STING
[C9orf72](/genes/c9orf72) haploinsufficiency impairs STING degradation through reduced autophagy, prolonging signaling
STING pathway genes are upregulated in ALS patient spinal cord microglia

Aging (Inflammaging)

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

Therapeutic Targeting

Small Molecule STING Inhibitors

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

Upstream cGAS Inhibitors

RU.521: Potent cGAS catalytic inhibitor; prevents cGAMP production
G150: cGAS inhibitor effective in mouse inflammation models

Clinical Considerations for Neurodegeneration

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

Pathway & Interaction Diagram

Interactive diagram showing STING1's key relationships in the SciDEX knowledge graph (15 connections shown).

Mermaid diagram (expand to render)

External Links

[UniProt: Q86WV6](https://www.uniprot.org/uniprot/Q86WV6)
[PDB: 6NT5](https://www.rcsb.org/structure/6NT5)
[InterPro: STING](https://www.ebi.ac.uk/interpro/entry/InterPro/IPR029158/)
[GeneCards: STING1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=STING1)

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)

[Gulen MF et al., cGAS-STING drives ageing-related inflammation and neurodegeneration (2023) (2023)](https://doi.org/10.1038/s41586-023-06373-1)

[Jin M et al., Tau activates microglia via the PQBP1-cGAS-STING pathway (2021) (2021)](https://doi.org/10.1038/s41593-021-00911-y)

[Unknown, Ablasser A & Chen ZJ, cGAS in action: expanding roles in immunity and inflammation (2019) (2019)](https://doi.org/10.1126/science.aat8657)

[Shang G et al., Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP (2019) (2019)](https://doi.org/10.1038/s41586-019-0998-5)

[McCauley ME et al., C9orf72 in myeloid cells suppresses STING-induced inflammation (2020) (2020)](https://doi.org/10.1038/s41586-020-2625-x)

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Related Entities

STING1PROTEIN

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slug	proteins-sting1-protein
kg_node_id	STING1PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-b7a775f9f3da
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-sting1-protein'}
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

95%

Debates

0

Incoming

19

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

STING Protein

STING Protein

Overview

STING Protein

Overview

Structure

Topology

Conformational Activation

Post-Translational Modifications

Normal Function

Innate Immune Sensing

Autophagy Induction

STING in the Brain

Role in Disease

Alzheimer's Disease

Parkinson's Disease

ALS/FTD

Aging (Inflammaging)

Therapeutic Targeting

Small Molecule STING Inhibitors

Upstream cGAS Inhibitors

Clinical Considerations for Neurodegeneration

Pathway & Interaction Diagram

See Also

External Links

References

💬 Discussion