Stimulator of interferon genes

Stimulator of interferon genes (STING), also known transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a is_associated_with::protein that in humans is encoded by the TMEM173 is_associated_with::gene.

STING plays an important role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens, such as is_associated_with::viruses, is_associated_with::mycobacteria and intracellular parasites. Type I interferon, mediated by STING, protects infected cells and nearby cells from local infection by binding to the same cell that secretes it (is_associated_with::autocrine signaling) and nearby cells (is_associated_with::paracrine signaling.)

STING is encoded by the TMEM173 gene. It works as both a direct cytosolic DNA sensor (CDS) and an is_associated_with::adaptor protein in Type I interferon signaling through different molecular mechanisms. It has been shown to activate downstream transcription factors is_associated_with::STAT6 and is_associated_with::IRF3 through TBK1, which are responsible for antiviral response and innate immune response against intracellular pathogen.

Structure
Amino acids 1–379 of human STING include the 4 transmembrane regions (TMs) and a C-terminal domain. The C-terminal domain (CTD: amino acids 138–379) contains the dimerization domain (DD) and the 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 is_associated_with::hydrophobic residues from each STING protomer form is_associated_with::hydrophobic interactions between each other at the interface.

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

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

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

Antiviral Immunity
STING elicits powerful type I interferon immunity against viral infection. After is_associated_with::viral entry, viral is_associated_with::nucleic acids will be present in the cytosol of infected cells. Several DNA sensors, such as DAI, is_associated_with::RNA polymerase III, is_associated_with::IFI16, is_associated_with::DDX41 and cGAS, can detect foreign is_associated_with::nucleic acids. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response.

Adenovirus, is_associated_with::herpes simplex virus, HSV-1 and HSV-2, as well as negative-stranded RNA virus-vesicular stomatitis virus (VSV) have been shown to be able to activate a STING-dependent is_associated_with::innate immune response.

Against intracellular bacteria
Intracellular bacteria, is_associated_with::Listeria monocytogenes, have been shown to stimulate host immune response through STING. STING may play an important role in the production of is_associated_with::MCP-1 and is_associated_with::CCL7 chemokines. STING deficient monocytes are intrinsically defective in migration to the liver during is_associated_with::Listeria monocytogenes infection. In this way, STING protects host from is_associated_with::Listeria monocytogenes infection by regulating is_associated_with::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 VSV, is_associated_with::HSV-1 and is_associated_with::Listeria monocytogenes, suggesting its potential correlation to human infectious diseases.

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

STING signaling mechanisms
STING mediates type I interferon immune response by functioning as both a direct DNA sensor and a signaling adaptor protein. Upon activation, STING stimulates TBK1 activity to phosphorylate is_associated_with::IRF3 or is_associated_with::STAT6. Phosphorylated IRF3s and STAT6s dimerize, and then enter nucleus to stimulate expression of genes involved in host immune response, such as IFNB, is_associated_with::CCL2, is_associated_with::CCL20, etc.

Several reports suggested that STING is associated with the activation of selective autophagy. is_associated_with::Mycobacterium tuberculosis has been shown to produce cytosolic DNA ligands which activate STING, resulting in is_associated_with::ubiquitination of bacteria and the subsequent recruitment of is_associated_with::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 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 is_associated_with::TBK1-is_associated_with::IRF3 and the downstream production of type I interferon. STING has been shown to bind directly to is_associated_with::cyclic di-GMP, and this recognition leads to the production of is_associated_with::cytokines, such as type I interferon, that are essential for successful pathogen elimination.

As a signaling adaptor
is_associated_with::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- DAI, is_associated_with::RNA polymerase III, is_associated_with::IFI16, have also been shown to activate STING through direct or indirect interactions.

is_associated_with::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 is_associated_with::cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP). After cyclic GMP-AMP bound STING is activated, it enhances is_associated_with::TBK1's activity to phosphorylate is_associated_with::IRF3 and is_associated_with::STAT6 for downstream is_associated_with::type I interferon response.