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Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
that in humans is encoded by the STING1
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. STING plays an important role in
innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
. STING induces
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
production when cells are infected with intracellular pathogens, such as
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room ...
,
mycobacteria ''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis (''M. tuberculosis'') and ...
and intracellular parasites.
Type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
, mediated by STING, protects infected cells and nearby cells from local infection by binding to the same cell that secretes it (
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
signaling) and nearby cells (
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
signaling.) It thus plays an important role, for instance, in controlling
norovirus Norovirus, sometimes referred to as the winter vomiting disease, is the most common cause of gastroenteritis. Infection is characterized by non-bloody diarrhea, vomiting, and stomach pain. Fever or headaches may also occur. Symptoms usually deve ...
infection. STING works as both a direct
cytosolic DNA sensor The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
(CDS) and an adaptor protein in
Type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
signaling through different molecular mechanisms. It has been shown to activate downstream transcription factors
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor co ...
and IRF3 through TBK1, which are responsible for antiviral response and innate immune response against
intracellular pathogen Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host. Types of parasites There are two main types of intracellular parasites: Facultative and Obligate. Facultative intracellular pa ...
.


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
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...
residues from each STING protomer form hydrophobic interactions between each other at the interface.


Expression

STING is expressed in
hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells ...
cells in peripheral lymphoid tissues, including T lymphocytes,
NK cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
,
myeloid cells A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...
and
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
. It has also been shown that STING is highly expressed in lung,
ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the bod ...
, heart,
smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...
,
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
,
bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...
and vagina.


Localization

The subcellular localization of STING has been elucidated as an
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
to perinuclear vesicles potentially involved in 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 The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
production in response to intracellular DNA and a variety of intracellular pathogens, including
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room ...
,
intracellular bacteria Intracellular bacteria are bacteria, which have the capability to enter and survive within the cells of the host organism. Many of them are capable of growth extracellularly, but some of them can grow and reproduce only intracellularly (obligate ...
and
intracellular parasite Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host. Types of parasites There are two main types of intracellular parasites: Facultative and Obligate. Facultative intracellular pa ...
s. Upon infection, STING from infected cells can sense the presence of
nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
from intracellular pathogens, and then induce interferon β and more than 10 forms of
interferon α The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyt ...
production.
Type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
produced by infected cells can find and bind to
Interferon-alpha/beta receptor The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ. ...
of nearby cells to protect cells from local infection.


Antiviral immunity

STING elicits powerful type I interferon immunity against viral infection. After
viral entry Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variat ...
, viral
nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
are present in the cytosol of infected cells. Several DNA sensors, such as DAI,
RNA polymerase III In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose ...
, IFI16,
DDX41 Probable ATP-dependent RNA helicase DDX41 is an enzyme that in humans is encoded by the ''DDX41'' gene. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number ...
and cGAS, can detect foreign
nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response. ''
Adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
'',
herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and ''Human alphaherpesvirus 2'', are two members of the Herpesviridae#Human herpesvirus types, human ''Herpesviridae'' family, a ...
, HSV-1 and HSV-2, as well as the negative-stranded RNA virus, vesicular stomatitis virus (VSV), have been shown to be able to activate a STING-dependent
innate immune response The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
. 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 ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the hos ...
'', have been shown to stimulate host immune response through STING. STING may play an important role in the production of
MCP-1 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. C ...
and CCL7 chemokines. STING deficient monocytes are intrinsically defective in migration to the liver during ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the hos ...
'' infection. In this way, STING protects host from ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the hos ...
'' infection by regulating
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
migration. The activation of STING is likely to be mediated by
cyclic di-AMP Cyclic di-AMP (also called c-di-AMP and c-di-adenosine monophosphate) is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum eu ...
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, HSV-1 and ''
Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the hos ...
'', 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
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
in host immunity mediated by STING. AT-rich stem-loop DNA motif in the ''
Plasmodium falciparum ''Plasmodium falciparum'' is a unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female '' Anopheles'' mosquito and causes the d ...
'' and '' Plasmodium berghei'' genome and extracellular DNA from '' Mycobacterium tuberculosis'' have been shown to activate
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
through STING. Perforation of the phagosome membrane mediated by
ESX1 Homeobox protein ESX1 is a protein that in humans is encoded by the ''ESX1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bi ...
secretion system allows extracellular mycobacterial DNA to access host cytosolic DNA sensors, thus inducing the production of
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
in macrophages. High
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
signature leads to the ''
M. tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'' pathogenesis and prolonged infection. STING-TBK1-IRF mediated
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
response is central to the pathogenesis of experimental cerebral malaria in laboratory animals infected with '' Plasmodium berghei''. Laboratory mice deficient in
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
response are resistant to experimental cerebral malaria.


STING signaling mechanisms

STING mediates
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
immune response by functioning as both a direct DNA sensor and a signaling adaptor protein. Upon activation, STING stimulates TBK1 activity to phosphorylate IRF3 or
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor co ...
. Phosphorylated IRF3s and STAT6s dimerize, and then enter nucleus to stimulate expression of genes involved in host immune response, such as IFNB,
CCL2 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. C ...
,
CCL20 Chemokine (C-C motif) ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakl ...
, 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 Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. F ...
of bacteria and the subsequent recruitment of
autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
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 TBK1- IRF3 and the downstream production of
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
. STING has been shown to bind directly to cyclic di-GMP, and this recognition leads to the production of cytokines, such as
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
, that are essential for successful pathogen elimination.


As a signaling adaptor

DDX41 Probable ATP-dependent RNA helicase DDX41 is an enzyme that in humans is encoded by the ''DDX41'' gene. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number ...
, 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,
RNA polymerase III In eukaryote cells, RNA polymerase III (also called Pol III) is a protein that transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose ...
, IFI16, have also been shown to activate STING through direct or indirect interactions.
Cyclic GMP-AMP synthase Cyclic GMP-AMP synthase (cGAS, Cyclic guanosine monophosphate–adenosine monophosphate, cGAMP synthase), belonging to the nucleotidyltransferase family, is a The cGAS – STING cytosolic DNA sensing pathway, cytosolic DNA sensor that activates a ...
(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 GMP-AMP bound STING is activated, it enhances TBK1's activity to phosphorylate IRF3 and
STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor co ...
for downstream
type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
response. It has been proposed that intracellular calcium plays an important role in the response of the STING pathway.


See also

*


References


Further reading

* * * * * * * * * {{Adaptor proteins Immune system Intracellular receptors