Alt. symbols: TMEM173 | FLJ38577 | NET23 | ERIS | MPYS | STING | MITA

Approved name: stimulator of interferon response cGAMP interactor 1
Alt. names: transmembrane protein 173 | stimulator of interferon genes, endoplasmic reticulum IFN stimulator

Location: 5q31.2: 139475533 - 139482935 (-)
Gene type: protein_coding, 22 transcripts.

Scores: LoFtool: 0.605000 | pLI: 0.03233062 | LOEUF: 0.903

HGNC: 27962

NCBI: 340061, RefSeq: NG_034249.1

Ensembl: ENSG00000184584.14

LRG_1308 | Status: public

OMIM: 612374

Expression | ProteinAtlas

STING1, formerly TMEM173, encodes STING (stimulator of interferon genes), a cytosolic DNA-sensing adaptor protein highly expressed in myeloid cells, NK cells, T cells, vascular endothelial cells, alveolar pneumocytes and bronchial epithelial cells (PMID: 33532887). When nucleic acid stimuli (i.e. pathogen-derived and mitochondrial DNA) bind to cGAMP synthase (cGAS), the latter produces cyclic GMP-AMP (cGAMP), which binds to STING, releasing it from its inhibitory C-terminal tail and promoting its polymerization, phosphorylation and activation. STING relocates from the ER membrane to the Golgi where it activates IKK and serine/threonine-protein kinase TBK1, eventually leading to IFN regulatory factor 3 (IRF3)-driven ISG expression and type I IFN production.

Heterozygous GOF mutations in STING1 cause SAVI (STING-associated vasculopathy with onset in infancy) [OMIM: 615934], characterized by fevers, failure to thrive, interstitial lung disease, and severe skin lesions. The last prominently involve the face, ears, nose, and digits, and result in ulceration, eschar formation, necrosis, and, in some cases, amputation. Polyarthritis, intracranial calcifications, glaucoma and immunodeficiency are less common features. Although most patients present in inf ancy, adult-onset disease has been reported (PMID: 33217613). Most patients will show increased peripheral blood expression of type I IFNs and ISGs, constitutive up-regulation of phosphorylated STAT1 in lymphocytes, and frequently harbor autoantibodies such as rheumatoid factor. Patients also present with T-cell defects, including low memory CD8+ cells and impaired T-cell proliferation in response to antigens. While JAK inhibition can be beneficial, especially when started early in the disease course, the extent of skin and lung disease cannot always be reversed. The first reported disease-causing variants were de novo missense changes residing in a highly conserved connector helix loop that controls the ligand-induced dimer rotation required for STING activation. Other variants that reside at the polymerization interface cause constitutive activation by exposing the polymerization interface and/or preventing inhibitor binding. Additionally, the Gly166Glu mutation, found in one family with chilblain lupus without fevers or lung disease, appears to strengthen dimer interface interactions via enhanced hydrogen bonding. Patients have also been reported to harbor multiple pathogenic variants in STING - one patient had 2 mutations in cis (PMID: 28041677), while 6 patients from 4 families were all homozygous for the R281W mutation (PMID: 32673614). This has led to the suggestion that some variants with a weaker effect on STING function might not be sufficient to individually cause disease but can do so in aggregate. Of note, the cGAS-STING pathway and dysregulated type I interferon signaling in general has been implicated in the pathogenesis of inflammatory bowel disease (IBD) via multiple mechanisms (PMID: 29281834, 30254094, 33577080, 34051146, 34453041). Though SAVI patients generally present with hypergammaglobulinemia, there are increasing links between chronic inflammation and humoral immunodeficiency, as illustrated by the number of systemic autoinflammatory disorder genes identified as mutated in patients with CVID diagnoses (PMID: 34489224, 33936634, 22236196, 32047491, 33843817), not to mention the multiple conditions featuring concurrent evidence of type I interferon activation and hypogammaglobulinemia such as LRBA deficiency (PMID: 31874111). Moreover, one study noted that 9 of their 10 SAVI patients showed low memory B-cell counts (PMID: 33217613). [Load More]