STING1
Available structures PDB Ortholog search:PDBeRCSB List of PDB id codes 4EF4,4EF5,4EMT,4EMU,4F5D,4F5E,4F5W,4F5Y,4F9E,4F9G,4KSY,4LOH,4LOI,4QXO,4QXP,4QXQ,4QXR,5BQX,5JEJ
Identifiers
Aliases	STING1, ERIS, MITA, MPYS, NET23, SAVI, STING, hMITA, hSTING, Stimulator of interferon genes, transmembrane protein 173, STING-beta, TMEM173, stimulator of interferon response cGAMP interactor 1
External IDs	OMIM:612374;MGI:1919762;HomoloGene:18868;GeneCards:STING1;OMA:STING1 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q31.2 Start 139,475,533bp[1] End 139,482,935bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18 B2|18 Start 35,866,732bp[2] End 35,873,607bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube olfactory zone of nasal mucosa granulocyte gastric mucosa right coronary artery upper lobe of left lung Descending thoracic aorta left uterine tube apex of heart ascending aorta Top expressed in lumbar spinal ganglion mesenteric lymph nodes endothelial cell of lymphatic vessel interventricular septum spleen tail of embryo blood thymus cervix internal carotid artery More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding cyclic-di-GMP binding protein homodimerization activity transcription factor binding protein binding identical protein binding protein kinase binding ubiquitin protein ligase binding 2',3'-cyclic GMP-AMP binding Cellular component cytoplasm integral component of membrane Golgi apparatus endoplasmic reticulum membrane membrane peroxisome mitochondrial outer membrane mitochondrion endoplasmic reticulum perinuclear region of cytoplasm cytoplasmic vesicle membrane plasma membrane secretory granule membrane Biological process interferon-beta production cellular response to interferon-beta immune system process regulation of type I interferon production defense response to virus cellular response to exogenous dsRNA activation of innate immune response positive regulation of protein binding positive regulation of transcription by RNA polymerase II positive regulation of defense response to virus by host apoptotic process innate immune response neutrophil degranulation cellular response to organic cyclic compound viral process positive regulation of DNA-binding transcription factor activity positive regulation of type I interferon production regulation of gene expression regulation of cellular metabolic process regulation of inflammatory response cytoplasmic pattern recognition receptor signaling pathway in response to virus Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 340061 72512 Ensembl ENSG00000184584 ENSG00000288243 ENSMUSG00000024349 UniProt Q86WV6 Q3TBT3 RefSeq (mRNA) NM_001301738 NM_198282 NM_001367258 NM_001289591 NM_001289592 NM_028261 RefSeq (protein) NP_001288667 NP_938023 NP_001354187 NP_001276520 NP_001276521 NP_082537 Location (UCSC) Chr 5: 139.48 – 139.48 Mb Chr 18: 35.87 – 35.87 Mb PubMed search [3] [4]
Wikidata
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Stimulator of interferon genes (STING), also known astransmembrane protein 173 (TMEM173) andMPYS/MITA/ERIS is aprotein that in humans is encoded by the STING1gene.^[5]

STING plays an important role ininnate immunity. STING inducestype I interferon production when cells are infected with intracellular pathogens, such asviruses,mycobacteria andintracellular parasites.^[6]Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection by binding to the same cell that secretes it (autocrine signaling) and nearby cells (paracrine signaling.) It thus plays an important role, for instance, in controllingnorovirus infection.^[7]

STING works as both a directcytosolic DNA sensor (CDS) and anadaptor protein inType I interferon signaling through different molecular mechanisms. It has been shown to activate downstream transcription factorsSTAT6 andIRF3 throughTBK1, which are responsible for antiviral response and innate immune response againstintracellular pathogen.^[8]

Amino acids 1–379 of human STING include the 4transmembrane regions (TMs) and aC-terminal domain. TheC-terminal domain (CTD: amino acids 138–379) contains the dimerization domain (DD) and thecarboxy-terminal tail (CTT: amino acids 340–379).^[8]

The STING forms a symmetrical dimer in the cell. STING dimer resembles a butterfly, with a deep cleft between the two protomers. Thehydrophobic residues from each STING protomer formhydrophobic interactions between each other at the interface.^[8][9]

STING is expressed inhematopoietic cells inperipheral lymphoid tissues, includingT lymphocytes,NK cells,myeloid cells andmonocytes. It has also been shown that STING is highly expressed in lung,ovary, heart,smooth muscle,retina,bone marrow and vagina.^[10][11]

The subcellular localization of STING has been elucidated as anendoplasmic reticulum protein. Also, it is likely that STING associates in close proximity withmitochondria associated ER membrane (MAM)-the interface between the mitochondrion and the ER.^[12] During intracellular infection, STING is able to relocalize fromendoplasmic reticulum toperinuclear vesicles potentially involved inexocyst mediated transport.^[12] STING has also been shown to colocalize with autophagy proteins,microtubule-associated protein 1 light chain 3 (LC3) andautophagy-related protein 9A, after double-stranded DNA stimulation, suggesting its presence in theautophagosome.^[13]

STING mediates thetype I interferon production in response to intracellular DNA and a variety of intracellular pathogens, includingviruses,intracellular bacteria andintracellular parasites.^[14] Upon infection, STING from infected cells can sense the presence ofnucleic acids from intracellular pathogens, and then induceinterferon β and more than 10 forms ofinterferon α production.Type I interferon produced by infected cells can find and bind toInterferon-alpha/beta receptor of nearby cells to protect cells from local infection.

STING elicits powerfultype I interferon immunity against viral infection. Afterviral entry, viralnucleic acids are present in the cytosol of infected cells. Several DNA sensors, such asDAI,RNA polymerase III,IFI16,DDX41 andcGAS, can detect foreignnucleic acids. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response.^[15]

Adenovirus,herpes simplex virus, HSV-1 and HSV-2, as well as thenegative-stranded RNA virus,vesicular stomatitis virus (VSV), have been shown to be able to activate a STING-dependentinnate immune response.^[14]

STING deficiency in mice led to lethal susceptibility to HSV-1 infection due to the lack of a successful type I interferon response.^[16]

Point mutation ofserine-358 dampens STING-IFN activation in bats and is suggested to give bats their ability to serve as reservoir hosts.^[17]

Intracellular bacteria,Listeria monocytogenes, have been shown to stimulate host immune response through STING.^[18] STING may play an important role in the production ofMCP-1 andCCL7 chemokines. STING deficient monocytes are intrinsically defective in migration to the liver duringListeria monocytogenes infection. In this way, STING protects host fromListeria monocytogenes infection by regulatingmonocyte migration. The activation of STING is likely to be mediated bycyclic di-AMP secreted by intracellular bacteria.^[18][19]

STING may be an important molecule for protective immunity against infectious organisms. For example, animals that cannot express STING are more susceptible to infection fromVSV,HSV-1 andListeria monocytogenes, suggesting its potential correlation to human infectious diseases.^[20]

Althoughtype I IFN is absolutely critical for resistance to viruses, there is growing literature about the negative role oftype I interferon in host immunity mediated by STING. AT-rich stem-loop DNA motif in thePlasmodium falciparum andPlasmodium berghei genome and extracellular DNA fromMycobacterium tuberculosis have been shown to activatetype I interferon through STING.^[21][22] Perforation of the phagosome membrane mediated byESX1 secretion system allows extracellular mycobacterial DNA to access host cytosolic DNA sensors, thus inducing the production oftype I interferon in macrophages. Hightype I interferon signature leads to theM. tuberculosis pathogenesis and prolonged infection.^[22] STING-TBK1-IRF mediatedtype I interferon response is central to the pathogenesis of experimental cerebral malaria in laboratory animals infected withPlasmodium berghei. Laboratory mice deficient intype I interferon response are resistant to experimental cerebral malaria.^[21]

STING mediatestype I interferon immune response by functioning as both a direct DNA sensor and asignaling adaptor protein. Upon activation, STING stimulatesTBK1 activity tophosphorylateIRF3 orSTAT6. Phosphorylated IRF3s and STAT6s dimerize, and then enter nucleus to stimulate expression of genes involved in host immune response, such asIFNB,CCL2,CCL20, etc.^[8][23]

Several reports suggested that STING is associated with the activation of selective autophagy.^[13]Mycobacterium tuberculosis has been shown to produce cytosolic DNA ligands which activate STING, resulting inubiquitination of bacteria and the subsequent recruitment ofautophagy related proteins, all of which are required for 'selective' autophagic targeting and innate defense againstM. tuberculosis.^[24]

In summary, STING coordinates multiple immune responses to infection, including the induction of interferons and STAT6-dependent response and selective autophagy response.^[8]

Cyclic dinucleotides-second-messenger signaling molecules produced by diverse bacterial species were detected in the cytosol of mammalian cells during intracellular pathogen infection; this leads to activation ofTBK1-IRF3 and the downstream production oftype I interferon.^[8][25]STING has been shown to bind directly tocyclic di-GMP, and this recognition leads to the production ofcytokines, such astype I interferon, that are essential for successful pathogen elimination.^[26]

DDX41, a member of the DEXDc family ofhelicases, inmyeloid dendritic cells recognizes intracellular DNA and mediates innate immune response through direct association with STING.^[27] Other DNA sensors-DAI,RNA polymerase III,IFI16, have also been shown to activate STING through direct or indirect interactions.^[15]

Cyclic GMP-AMP synthase (cGAS), which belongs to thenucleotidyltransferase family, is able to recognize cytosolic DNA contents and induce STING-dependent interferon response by producing secondary messengercyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP). Aftercyclic GMP-AMP bound STING is activated, it enhancesTBK1's activity to phosphorylateIRF3 andSTAT6 for downstreamtype I interferon response.^[28][29]

It has been proposed that intracellular calcium plays an important role in the response of the STING pathway.^[30]

• STING agonist – Component of the innate immune systemPages displaying short descriptions of redirect targets

• Genes on human chromosome 5
• Immune system
• Intracellular receptors

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• Pages displaying short descriptions of redirect targets via Module:Annotated link