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 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. [1]
| Property | Value | [2]
|----------|-------| [3]
| Gene Symbol | TMEM173 |
| Full Name | Stimulator of Interferon Genes (STING) |
| Chromosomal Location | 5q31.2 |
| NCBI Gene ID | 340061 |
| OMIM ID | 612374 |
| Ensembl ID | ENSG00000184515 |
| UniProt ID | Q86WV1 |
| Encoded Protein | STING |
| Protein Size | 379 amino acids (~42 kDa) |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, ALS, systemic lupus erythematosus, Aicardi-Goutières syndrome |
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).
The cGAS-STING pathway represents a major cytosolic DNA sensing mechanism:
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 signaling, promoting inflammatory cytokine expression.
STING activation induces 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.
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.
The cGAS-STING pathway is chronically activated in Alzheimer's disease brain tissue. Aβ 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:
Genome-wide association studies have identified STING variants that modify AD risk, highlighting its relevance to disease pathogenesis.
STING activation in Parkinson's disease is associated with:
In ALS, STING activation occurs in microglia and astrocytes:
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.
TMEM173 is widely expressed across tissues:
The STING pathway is being targeted for neurodegenerative disease treatment: