Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a
protein that in humans is encoded by the STING1
gene.[5]
STING plays an important role in
innate immunity. STING induces
type I interferon production when cells are infected with intracellular pathogens, such as
viruses,
mycobacteria and
intracellular 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 controlling
norovirus infection.[7]
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.[8][9]
STING elicits powerful
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
DAI,
RNA polymerase III,
IFI16,
DDX41 and
cGAS, can detect foreign
nucleic acids. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response.[15]
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 of serine-358 dampens STING-IFN activation in bats and is suggested to give bats their ability to serve as reservoir hosts.[17]
Against intracellular bacteria
Intracellular bacteria, Listeria monocytogenes, have been shown to stimulate host immune response through STING.[18] 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.[18][19]
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, suggesting its potential correlation to human infectious diseases.[20]
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 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.[21][22] 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.[22] 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.[21]
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
IRF3 or
STAT6. Phosphorylated IRF3s and STAT6s dimerize, and then enter nucleus to stimulate expression of genes involved in host immune response, such as
IFNB,
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 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.[24]
In summary, STING coordinates multiple immune responses to infection, including the induction of interferons and STAT6-dependent response and selective autophagy response.[8]
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.[8][25]
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, that are essential for successful pathogen elimination.[26]
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.[27] Other DNA sensors-
DAI,
RNA polymerase III,
IFI16, have also been shown to activate STING through direct or indirect interactions.[15]
^
abcdefBurdette DL, Vance RE (Jan 2013). "STING and the innate immune response to nucleic acids in the cytosol". Nature Immunology. 14 (1): 19–26.
doi:
10.1038/ni.2491.
PMID23238760.
S2CID7968532.