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TMEM173

Official Full Name
stimulator of interferon response cGAMP interactor 1
Organism
Homo sapiens
GeneID
340061
Background
This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses. The encoded protein has also been shown to play a role in apoptotic signaling by associating with type II major histocompatibility complex. Mutations in this gene are the cause of infantile-onset STING-associated vasculopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]
Synonyms
ERIS; MITA; MPYS; SAVI; NET23; STING; hMITA; hSTING; TMEM173; STING-beta;
Bio Chemical Class
TMEM173 family
Protein Sequence
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS
Open
Disease
Head and neck cancer, Inborn purine/pyrimidine/nucleotide metabolism error, Lymphoma, Melanoma, Metastatic lymph node neoplasm, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
15 +
Discontinued Drug
0

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Detailed Information

The TMEM173 gene, also known as STING1, is located on human chromosome 5q35.1 and encodes a five-transmembrane protein of 379 amino acids with an approximate molecular weight of 42 kDa. Multiple splicing variants have been identified, and its promoter region contains interferon-stimulated response elements (ISRE), suggesting transcriptional regulation by interferon signaling. STING is predominantly localized to the endoplasmic reticulum (ER) membrane and is highly expressed in immune cells such as dendritic cells and macrophages, as well as in epithelial cells. Structurally, it consists of an N-terminal transmembrane domain and a C-terminal cytosolic domain, which forms a dimeric binding pocket for cyclic dinucleotides (CDNs) — a key step for downstream activation.

Biological Function and Molecular Mechanisms

STING is a central pattern recognition receptor (PRR) in the innate immune system, responsible for sensing cytosolic DNA of pathogenic origin (from viruses or bacteria) or endogenous sources (such as mitochondrial leakage). Its activation involves a multistep process:

  1. Ligand Recognition: Cytosolic DNA is detected by the enzyme cGAS, which catalyzes the production of the secondary messenger 2′3′-cGAMP. This molecule binds to the C-terminal domain of STING, inducing a conformational change and oligomerization.
  2. Subcellular Trafficking: Activated STING translocates from the ER to the Golgi apparatus, where it recruits TBK1 kinase. TBK1 phosphorylates the pLxIS motif of STING, enabling the recruitment of transcription factors such as IRF3 and NF-κB.
  3. Downstream Signaling: Phosphorylated IRF3 and NF-κB translocate to the nucleus to drive the expression of type I interferons (IFN-α/β) and pro-inflammatory cytokines (such as TNF-α and IL-6), establishing an antiviral state.

Beyond its role in innate immunity, STING directly regulates autophagy. Upon binding cGAMP, STING associates with the ER–Golgi intermediate compartment (ERGIC) and recruits autophagy-related proteins such as WIPI2 and LC3. This process promotes autophagosome formation and facilitates the clearance of intracellular pathogens or damaged DNA, functioning independently of TBK1 phosphorylation and illustrating the multifunctional nature of STING.

Figure 1. The CGAS-STING1 pathway.Figure 1. The CGAS-STING1 pathway. (Zhang R, et al., 2021)

Genetic Disorders

Gain-of-function mutations in STING1 (such as p.V155M or p.N154S) are linked to STING-associated vasculopathy with onset in infancy (SAVI), characterized by systemic vasculitis, pulmonary fibrosis, and skin ulcerations. These mutations lead to constitutive STING activation, triggering type I interferon signaling even in the absence of ligand binding. Targeted inhibition of the downstream pathway, for example, with JAK inhibitors, has shown partial symptom relief in affected patients.

Infectious Diseases and Antiviral Immunity

STING is a key defense component against DNA viruses, including herpesviruses and poxviruses. Many viruses have evolved strategies to evade STING-mediated signaling. For instance, the E7 protein of human papillomavirus binds to STING and prevents its dimerization, while adenoviral proteins suppress cGAMP synthesis. In bacterial infections, STING can sense cyclic dinucleotides, such as c-di-GMP, produced by Gram-positive bacteria, thereby initiating autophagy-dependent bacterial clearance.

Dual Roles in Tumor Immunity

STING signaling exerts context-dependent effects in cancer. Chronic activation can promote an immunosuppressive microenvironment by inducing T-cell apoptosis and expanding myeloid-derived suppressor cells (MDSCs). Conversely, pharmacological activation of STING can enhance tumor antigen presentation and synergize with immune checkpoint blockade, offering promising therapeutic potential. However, epigenetic silencing of STING expression, such as promoter methylation, may limit its effectiveness in certain solid tumors.

Autoimmune and Neurodegenerative Diseases

Aberrant activation of the cGAS–STING pathway contributes to autoimmune diseases such as systemic lupus erythematosus (SLE), where self-DNA triggers excessive interferon production. STING deficiency in preclinical models alleviates lupus-associated kidney damage. In neurodegenerative conditions like Parkinson's disease, aggregated α-synuclein activates STING, promoting microglia-driven neuroinflammation. STING inhibition has demonstrated neuroprotective effects in experimental settings.

Research Advances and Therapeutic Perspectives

Current therapeutic strategies targeting the STING pathway fall into two main categories:

  • Agonists: Synthetic CDN analogs and non-nucleotide small molecules have been developed to activate STING signaling. These agents are being investigated for intratumoral or systemic administration to boost antitumor immunity.
  • Inhibitors: For interferonopathies and conditions such as SAVI, small molecules that covalently modify STING cysteine residues to block oligomerization have shown potential in preclinical and early clinical studies.

Additionally, the link between STING and autophagy provides new therapeutic avenues for infectious diseases. Enhancing STING-dependent autophagy has been explored as a strategy to improve pathogen clearance, including in infections caused by Mycobacterium tuberculosis.

In summary, STING serves as a pivotal sensor and effector in innate immunity, bridging nucleic acid recognition with inflammatory, autophagic, and adaptive immune responses. Its multifaceted roles in infection, cancer, autoimmunity, and neurodegeneration make it a compelling therapeutic target with expanding translational potential.

Reference

  1. Zhang R, Kang R, Tang D. The STING1 network regulates autophagy and cell death. Signal Transduct Target Ther. 2021 Jun 2;6(1):208.
  2. Zhang R, Kang R, Tang D. STING1 in Different Organelles: Location Dictates Function. Front Immunol. 2022 Mar 17;13:842489.
  3. Zhang RX, Kang R, Tang DL. STING1 in sepsis: Mechanisms, functions, and implications. Chin J Traumatol. 2022 Jan;25(1):1-10.
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