Phospho-TMEM173 (Ser366)

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]

TMEM173 Gene(Protein Coding) Transmembrane Protein 173

Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:18724357, PubMed:18818105, PubMed:19433799, PubMed:19776740, PubMed:23027953, PubMed:23910378, PubMed:23747010, PubMed:29973723, PubMed:30842659, PubMed:35045565).
Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (PubMed:26300263).
Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol (PubMed:21947006, PubMed:23258412, PubMed:23707065, PubMed:23722158, PubMed:26229117, PubMed:23910378, PubMed:23747010, PubMed:30842659).
Upon binding of c-di-GMP or cGAMP, STING1 oligomerizes, translocates from the endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent anti-viral state (PubMed:22394562, PubMed:25636800, PubMed:29973723, PubMed:30842653, PubMed:35045565).
In addition to promote the production of type I interferons, plays a direct role in autophagy (PubMed:30568238, PubMed:30842662).
Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (PubMed:30842662).
The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome (PubMed:30842662).
The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (PubMed:30568238, PubMed:30842662).
Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (By similarity).
Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263, PubMed:23910378, PubMed:23747010).
The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (PubMed:26150511).
May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (PubMed:18724357).
May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity).
(Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein (PubMed:26405230).
Such oncoproteins prevent the ability to sense cytosolic DNA (PubMed:26405230).

Activation of innate immune responseManual Assertion Based On ExperimentIDA:ComplexPortal
Autophagosome assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to exogenous dsRNAManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to interferon-betaIEA:Ensembl
Cellular response to organic cyclic compoundManual Assertion Based On ExperimentIDA:UniProtKB
Defense response to virusManual Assertion Based On ExperimentIDA:UniProtKB
Innate immune responseManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of defense response to virus by hostManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of DNA-binding transcription factor activityManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of interferon-beta productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of macroautophagyManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of protein bindingManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of type I interferon productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of type I interferon-mediated signaling pathwayManual Assertion Based On ExperimentIDA:ComplexPortal
Protein complex oligomerizationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of inflammatory responseIEA:Ensembl
ReticulophagyISS:UniProtKB

Endoplasmic reticulum membrane
Cytoplasm, perinuclear region
Endoplasmic reticulum-Golgi intermediate compartment membrane
Golgi apparatus membrane
Cytoplasmic vesicle, autophagosome membrane
Mitochondrion outer membrane
Cell membrane
In response to double-stranded DNA stimulation, translocates from the endoplasmic reticulum through the endoplasmic reticulum-Golgi intermediate compartment and Golgi to post-Golgi vesicles, where the kinase TBK1 is recruited (PubMed:19433799, PubMed:30842659, PubMed:30842653, PubMed:29694889).
Upon cGAMP-binding, translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in a process that is dependent on COPII vesicles; STING1-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis (PubMed:30842662).

STING-associated vasculopathy, infantile-onset (SAVI):
An autoinflammatory disease characterized by early-onset systemic inflammation and cutaneous vasculopathy, resulting in severe skin lesions. Violaceous, scaling lesions of fingers, toes, nose, cheeks and ears progress to acral necrosis in most of the patients. Some patients have severe interstitial lung disease.

Cytoplasmic: 1-17
Helical: 18-34
Lumenal: 35-44
Helical: 45-69
Cytoplasmic: 70-91
Helical: 92-106
Lumenal: 107-116
Helical: 117-134
Cytoplasmic: 135-379

Phosphorylation by TBK1 leads to activation and production of IFN-beta (PubMed:18818105, PubMed:19433799, PubMed:25636800, PubMed:30842659, PubMed:30842653, PubMed:27302953).
Following cyclic nucleotide (c-di-GMP or cGAMP)-binding, activation and translocation from the endoplasmic reticulum, STING1 is phosphorylated by TBK1 at Ser-366 in the pLxIS motif (PubMed:25636800, PubMed:32690950).
The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800).
The phosphorylated pLxIS motif facilitates SENP2 recruitment during late phase of viral infection (By similarity).
Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity).
Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta (PubMed:32753499).
Phosphorylation at Ser-358 is also required to activate IRF3 (PubMed:25636800).
Ubiquitinated (PubMed:19285439, PubMed:19433799, PubMed:21074459, PubMed:25254379).
Ubiquitinated via 'Lys-63'-linked ubiquitin chains in response to double-stranded DNA treatment, leading to relocalization to autophagosomes and subsequent degradation; this process is dependent on SQSTM1 (By similarity).
'Lys-63'-linked ubiquitination mediated by TRIM56 at Lys-150 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta (PubMed:21074459).
'Lys-48'-linked polyubiquitination at Lys-150 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation (PubMed:19285439).
'Lys-11'-linked polyubiquitination at Lys-150 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination (PubMed:25254379).By Similarity4 Publications
Sumoylated at Lys-338 by TRIM38 during the early phase of viral infection, promoting its stability by preventing its relocalization to autophagosomes and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection.By Similarity
Palmitoylation takes place in the Golgi apparatus and creates a platform for the recruitment of TBK1.