Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a regulator protein that in humans is encoded by the STING1 gene. STING plays an important role in Innate immune system, innate immunity. STING induces Interferon type I, type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria and parasite, intracellular parasites. Interferon type I, 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 controlling norovirus infection. STING works as both a direct The cGAS – STING cytosolic DNA sensing pathway, cytosolic DNA sensor (CDS) and an Signal transducing adaptor protein, adaptor protein in Interferon type I, Type I interferon signaling through different molecular mechanisms. It has been shown to activate downstream transcription factors STAT6 and IRF3 through TANK-binding kinase 1, TBK1, which are responsible for antiviral response and innate immune response against Intracellular parasite, intracellular pathogen.

Structure

Amino acids 1–379 of human STING include the 4 Transmembrane region#Transmembrane domain, transmembrane regions (TMs) and a C-terminus#C-terminal domain, C-terminal domain. The C-terminus#C-terminal domain, C-terminal domain (CTD: amino acids 138–379) contains the dimerization domain (DD) and the C-terminus, carboxy-terminal tail (CTT: amino acids 340–379). The STING forms a symmetrical dimer in the cell. STING dimer resembles a butterfly, with a deep cleft between the two protomers. The hydrophobic residues from each STING protomer form hydrophobic interactions between each other at the interface.

Expression

STING is expressed in hematopoietic cells in Lymphoid tissue#Lymphoid tissue, peripheral lymphoid tissues, including T lymphocytes, NK cells, myeloid cells and monocytes. It has also been shown that STING is highly expressed in lung, ovary, heart, smooth muscle, retina, bone marrow and vagina.

Localization

The subcellular localization of STING has been elucidated as an endoplasmic reticulum protein. Also, it is likely that STING associates in close proximity with Mitochondrion#Mitochondria-associated ER membrane (MAM), mitochondria associated ER membrane (MAM)-the interface between the mitochondrion and the ER. During intracellular infection, STING is able to relocalize from endoplasmic reticulum to Transport vesicle#Transport vesicles, perinuclear vesicles potentially involved in exocyst mediated transport. STING has also been shown to colocalize with autophagy proteins, MAP1LC3A, microtubule-associated protein 1 light chain 3 (LC3) and ATG9A, autophagy-related protein 9A, after double-stranded DNA stimulation, suggesting its presence in the autophagy, autophagosome.

Function

STING mediates the Interferon type I, type I interferon production in response to intracellular DNA and a variety of intracellular pathogens, including viruses, Intracellular parasite, intracellular bacteria and intracellular parasites. Upon infection, STING from infected cells can sense the presence of nucleic acids from intracellular pathogens, and then induce Interferon type I#IFN-β, interferon β and more than 10 forms of Interferon type I#IFN-α, interferon α production. Interferon type I, Type I interferon produced by infected cells can find and bind to Interferon-alpha/beta receptor of nearby cells to protect cells from local infection.

Antiviral immunity

STING elicits powerful Interferon type I, type I interferon immunity against viral infection. After viral entry, viral nucleic acids are present in the cytosol of infected cells. Several DNA sensors, such as ZBP1, DAI, RNA polymerase III, IFI16, DDX41 and Cyclic GMP-AMP synthase, cGAS, can detect foreign nucleic acids. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response. ''Adenoviridae, Adenovirus'', herpes simplex virus, HSV-1 and HSV-2, as well as the RNA virus#Single-stranded RNA viruses and RNA Sense, negative-stranded RNA virus, vesicular stomatitis virus (VSV), have been shown to be able to activate a STING-dependent innate immune response. STING deficiency in mice led to lethal susceptibility to HSV-1 infection due to the lack of a successful type I interferon response. Point mutation of serine-358 dampens STING-IFN activation in bats and is suggested to give bats their ability to serve as reservoir hosts.

Against intracellular bacteria

Intracellular bacteria, ''Listeria monocytogenes'', have been shown to stimulate host immune response through STING. STING may play an important role in the production of MCP-1 and CCL7 chemokines. STING deficient monocytes are intrinsically defective in migration to the liver during ''Listeria monocytogenes'' infection. In this way, STING protects host from ''Listeria monocytogenes'' infection by regulating monocyte migration. The activation of STING is likely to be mediated by cyclic di-AMP secreted by intracellular bacteria.

Other

STING may be an important molecule for protective immunity against infectious organisms. For example, animals that cannot express STING are more susceptible to infection from Vesicular stomatitis virus, VSV, HSV-1 and ''Listeria monocytogenes'', suggesting its potential correlation to human infectious diseases.

Role in host immunity

Although type I interferon, type I IFN is absolutely critical for resistance to viruses, there is growing literature about the negative role of type I interferon in host immunity mediated by STING. AT-rich stem-loop DNA motif in the ''Plasmodium falciparum'' and ''Plasmodium berghei'' genome and extracellular DNA from ''Mycobacterium tuberculosis'' have been shown to activate type I interferon through STING. Perforation of the phagosome membrane mediated by ESX1 secretion system allows extracellular mycobacterial DNA to access host cytosolic DNA sensors, thus inducing the production of type I interferon in macrophages. High type I interferon signature leads to the ''M. tuberculosis'' pathogenesis and prolonged infection. STING-TBK1-IRF mediated type I interferon response is central to the pathogenesis of experimental cerebral malaria in laboratory animals infected with ''Plasmodium berghei''. Laboratory mice deficient in type I interferon response are resistant to experimental cerebral malaria.

STING signaling mechanisms

STING mediates Interferon type I, type I interferon immune response by functioning as both a direct DNA sensor and a Signal transducing adaptor protein, signaling adaptor protein. Upon activation, STING stimulates TANK-binding kinase 1, TBK1 activity to Protein phosphorylation, phosphorylate IRF3 or STAT6. Phosphorylated IRF3s and STAT6s dimerize, and then enter nucleus to stimulate expression of genes involved in host immune response, such as Interferon beta, IFNB, CCL2, CCL20, etc. Several reports suggested that STING is associated with the activation of selective autophagy. ''Mycobacterium tuberculosis'' has been shown to produce cytosolic DNA ligands which activate STING, resulting in ubiquitination of bacteria and the subsequent recruitment of autophagy related proteins, all of which are required for 'selective' autophagic targeting and innate defense against ''M. tuberculosis''. In summary, STING coordinates multiple immune responses to infection, including the induction of interferons and STAT6-dependent response and selective autophagy response.

As a cytosolic DNA sensor

Cyclic nucleotide, 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 of TANK-binding kinase 1, TBK1-IRF3 and the downstream production of Interferon type I, type I interferon. STING has been shown to bind directly to cyclic di-GMP, and this recognition leads to the production of cytokines, such as Interferon type I, type I interferon, that are essential for successful pathogen elimination.

As a signaling adaptor

DDX41, a member of the DEXDc family of helicases, in myeloid dendritic cells recognizes intracellular DNA and mediates innate immune response through direct association with STING. Other DNA sensors- ZBP1, DAI, RNA polymerase III, IFI16, have also been shown to activate STING through direct or indirect interactions. Cyclic GMP-AMP synthase (cGAS), which belongs to the nucleotidyltransferase family, is able to recognize cytosolic DNA contents and induce STING-dependent interferon response by producing secondary messenger cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP). After cyclic guanosine monophosphate–adenosine monophosphate, cyclic GMP-AMP bound STING is activated, it enhances TANK-binding kinase 1, TBK1's activity to phosphorylate IRF3 and STAT6 for downstream type I interferon response. It has been proposed that intracellular calcium plays an important role in the response of the STING pathway.