TMEM173 (STING)

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TMEM173 (STING)

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TMEM173 (STING)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>TMEM173</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Stimulator of Interferon Genes (STING)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q31.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>340061</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>612374</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000184515</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q86WV1</td>
</tr>
<tr>
<td class="label">Encoded Protein</td>
<td>STING</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>379 amino acids (~42 kDa)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, ALS, systemic lupus erythematosus, Aicardi-Goutières syndrome</td>
</tr>
</table>

...

TMEM173 (STING)

Introduction

TMEM173, also known as STING (Stimulator of Interferon Genes), is a critical innate immune receptor that plays a central role in detecting cytosolic DNA and initiating type I interferon responses. Originally characterized for its antiviral functions, STING has emerged as a key player in neuroinflammation and neurodegeneration. Dysregulation of the cGAS-[STING pathway](/entities/sting-pathway) has been implicated in Alzheimer's disease, Parkinson's disease, ALS, and multiple sclerosis. This page covers TMEM173 structure, function, disease associations, and therapeutic targeting. [@ishikawa2008]

Overview

Mermaid diagram (expand to render)

Structure and Mechanism

Domain Architecture

STING is a transmembrane protein localized primarily to the endoplasmic reticulum (ER) membrane. It contains four transmembrane helices at the N-terminus that anchor it to the ER membrane, followed by a cytosolic ligand-binding domain (LBD) and a C-terminal tail (CTT). The cytosolic domain adopts a dimeric architecture that undergoes conformational changes upon ligand binding, transitioning from an inactive open state to an active closed state.

The ligand-binding domain binds cyclic dinucleotides (cDNGs) including cyclic GMP-AMP (cGAMP), which is produced by the enzyme cGAS (cyclic GMP-AMP synthase) upon detection of cytosolic DNA. cGAMP binding triggers STING dimerization and translocation from the ER to the Golgi apparatus, where it recruits and activates TBK1 (TANK-binding kinase 1).

cGAS-STING Pathway

The cGAS-STING pathway represents a major cytosolic DNA sensing mechanism:

cytosolic DNA binds to cGAS, inducing a conformational change that enables cGAMP synthesis

cGAMP binds to STING, causing dimerization and activation

Activated STING recruits TBK1 via the C-terminal tail

TBK1 phosphorylates STING and the transcription factor IRF3

Phosphorylated IRF3 dimerizes and translocates to the nucleus

IRF3 induces expression of type I interferons (IFN-α, IFN-β) and other interferon-stimulated genes (ISGs)

Normal Physiological Functions

Innate Immune Defense

STING is essential for antiviral immunity against DNA viruses (herpesviruses, adenoviruses) and some bacteria. Activation leads to rapid production of type I interferons that establish an antiviral state in neighboring cells. STING also activates [NF-κB](/entities/nf-kb) signaling, promoting inflammatory cytokine expression.

Autophagy Regulation

STING activation induces [autophagy](/entities/autophagy), which can be either protective (eliminating pathogens, damaged organelles) or detrimental (disrupting cellular homeostasis). The relationship between STING and autophagy is context-dependent and involves complex signaling cross-talk.

Cellular Homeostasis

STING is involved in cellular stress responses, including ER stress and mitochondrial dysfunction. These connections are particularly relevant to neurodegeneration, where cellular stress is a hallmark feature.

Disease Associations

Alzheimer's Disease

The cGAS-STING pathway is chronically activated in Alzheimer's disease brain tissue. [Aβ](/proteins/amyloid-beta) plaques and oligomers trigger microglial activation through DNA release into the cytosol, activating cGAS and subsequent STING-dependent type I interferon responses. This chronic interferon signaling contributes to:

Dysregulated microglial phenotypes
Synaptic pruning abnormalities
Impaired phagocytosis
Neurotoxicity

Genome-wide association studies have identified STING variants that modify AD risk, highlighting its relevance to disease pathogenesis.

Parkinson's Disease

STING activation in Parkinson's disease is associated with:

Mitochondrial DNA release into cytosol (due to mitochondrial dysfunction)
Chronic neuroinflammation in substantia nigra and striatum
Microglial activation contributing to dopaminergic neuron loss
Interaction with α-synuclein pathology

Amyotrophic Lateral Sclerosis (ALS)

In ALS, STING activation occurs in [microglia](/cell-types/microglia-neuroinflammation) and [astrocytes](/entities/astrocytes):

[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology triggers DNA sensing pathway activation
[C9orf72](/entities/c9orf72) mutations (a major ALS gene) dysregulate STING signaling
STING-dependent inflammation contributes to motor neuron death

Aicardi-Goutières Syndrome

This autoimmune disorder features constitutive STING activation due to mutations in TREX1 (which normally degrades cytosolic DNA), leading to chronic interferon production and neurological deterioration.

Expression

TMEM173 is widely expressed across tissues:

Brain: [Neurons](/entities/neurons), astrocytes, microglia, oligodendrocytes
Highest expression: Microglia and immune cells
Expression increases: With age and in neurodegenerative disease states

Key Publications

[Crow et al., STING in neurodegeneration (2024)](https://doi.org/10.1038/s41582-024-00867-8)

[Chen et al., cGAS-STING in Alzheimer's disease (2023)](https://doi.org/10.1038/s41586-023-05712-4)

[Sliter et al., STING and mitophagy in Parkinson's disease (2018)](https://doi.org/10.1038/s41586-018-0448-9)

Therapeutic Targeting

The STING pathway is being targeted for neurodegenerative disease treatment:

STING inhibitors: H-151, C-176, C-178 reduce neuroinflammation in preclinical models
cGAS inhibitors: RU.521 blocks upstream activation
Antisense oligonucleotides: Reduce STING expression

Cross-References

[cGAS](/genes/cgas) — Cyclic GMP-AMP synthase
[TBK1](/genes/tbk1) — TANK-binding kinase 1
[TREM2](/genes/trem2) — Microglial receptor implicated in AD
[Alpha-Synuclein](/proteins/alpha-synuclein) — Protein aggregation in PD
[Microglia](/cell-types/microglia) — Brain immune cells
[Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory mechanisms in neurodegeneration

External Links

[National Institute on Aging (NIA)](https://www.nia.nih.gov/health/alzheimers)
[Alzheimer's Association](https://www.alz.org/)
[Michael J. Fox Foundation for Parkinson's Research](https://www.michaeljfox.org/)
[ALS Association](https://www.als.org/)
[Cure Huntington's Disease Initiative (CHDI)](https://www.hdinsight.org/)
[National Institute of Neurological Disorders and Stroke (NINDS)](https://www.ninds.nih.gov/)

References

[Unknown, Ishikawa & Barber, STING regulates innate immune responses (2008) (2008)](https://doi.org/10.1038/nature07317)

[Sun et al., STING is a direct adaptor for TBK1 in antiviral immunity (2013) (2013)](https://doi.org/10.1038/nature12714)

[Unknown, Barber, STING-dependent signaling and innate immunity (2015) (2015)](https://doi.org/10.1016/j.tics.2015.03.002)

Pathway Diagram

The following diagram shows the key molecular relationships involving TMEM173 (STING) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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TMEM173 (STING)

TMEM173 (STING)

Introduction

TMEM173 (STING)

Introduction

Overview

Structure and Mechanism

Domain Architecture

cGAS-STING Pathway

Normal Physiological Functions

Innate Immune Defense

Autophagy Regulation

Cellular Homeostasis

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Aicardi-Goutières Syndrome

Expression

Key Publications

Therapeutic Targeting

Cross-References

See Also

External Links

References

Pathway Diagram