Stimulator of interferon genes

Transmembrane protein 173

STING crystal structure created by PDB protein workshop rendering PDB: 4EMU, adapted from
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsTMEM173 ; ERIS; MITA; MPYS; NET23; STING
External IDsOMIM: 612374 HomoloGene: 18868 GeneCards: TMEM173 Gene
Orthologs
SpeciesHumanMouse
Entrez34006172512
EnsemblENSG00000184584ENSMUSG00000024349
UniProtQ86WV6Q3TBT3
RefSeq (mRNA)NM_198282NM_028261
RefSeq (protein)NP_938023NP_082537
Location (UCSC)Chr 5:
138.86 – 138.86 Mb		Chr 18:
35.73 – 35.74 Mb
PubMed search

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

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.[1] 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.)

STING is encoded by the TMEM173 gene.[2] It works as both a direct cytosolic DNA sensor (CDS) and an adaptor protein in Type I interferon signaling through different molecular mechanisms. It has been shown to activate downstream transcription factors STAT6 and IRF3 through TBK1, which are responsible for antiviral response and innate immune response against intracellular pathogen.[3]

Structure

Human STING Protein Architecture

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).[3]

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.[3][4]

Expression

STING is expressed in hematopoietic cells in 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.[5] [6]

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 mitochondria associated ER membrane (MAM)-the interface between the mitochondrion and the ER.[7] During intracellular infection, STING is able to relocalize from endoplasmic reticulum to perinuclear vesicles potentially involved in exocyst mediated transport.[7] 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.[8]

Function

STING mediates the type I interferon production in response to intracellular DNA and a variety of intracellular pathogens, including viruses, intracellular bacteria and intracellular parasites.[9] Upon infection, STING from infected cells can sense the presence of 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 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 viral entry, viral nucleic acids will be 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.[10]

Adenovirus, 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 innate immune response.[9]

Against intracellular bacteria

Intracellular bacteria, Listeria monocytogenes, have been shown to stimulate host immune response through STING.[11] 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.[11][12]

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.[13]

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.[14] [15] 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.[15] 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.[14]

STING signaling mechanisms

STING signaling

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.[3][16]

Several reports suggested that STING is associated with the activation of selective autophagy.[8] 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.[17]

In summary, STING coordinates multiple immune responses to infection, including the induction of interferons and STAT6-dependent response and selective autophagy response.[3]

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.[3][18] 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.[19]

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.[20] Other DNA sensors- DAI, RNA polymerase III, IFI16, have also been shown to activate STING through direct or indirect interactions.[10]

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 GMP-AMP bound STING is activated, it enhances TBK1's activity to phosphorylate IRF3 and STAT6 for downstream type I interferon response.[21][22]

References

  1. ↑ Nakhaei P, Hiscott J, Lin R (June 2010). "STING-ing the antiviral pathway". J Mol Cell Biol 2 (3): 110–2. doi:10.1093/jmcb/mjp048. PMID 20022884.
  2. ↑ "Entrez Gene: TMEM173 transmembrane protein 173".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Burdette DL, Vance RE (January 2013). "STING and the innate immune response to nucleic acids in the cytosol". Nat. Immunol. 14 (1): 19–26. doi:10.1038/ni.2491. PMID 23238760.
  4. ↑ Shu C, Yi G, Watts T, Kao CC, Li P (July 2012). "Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system". Nat. Struct. Mol. Biol. 19 (7): 722–4. doi:10.1038/nsmb.2331. PMC 3392545. PMID 22728658.
  5. ↑ "EST expression profile of TMEM173". biogps org. biogps.org.
  6. ↑ "NCBI TMEM173 expression GEOprofile". NCBI. www.ncbi.nlm.nih.gov/geoprofiles.
  7. ↑ 7.0 7.1 Ishikawa H, Barber GN (October 2008). "STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling". Nature 455 (7213): 674–8. doi:10.1038/nature07317. PMC 2804933. PMID 18724357.
  8. ↑ 8.0 8.1 Saitoh T, Fujita N, Hayashi T et al. (December 2009). "Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response". Proc. Natl. Acad. Sci. U.S.A. 106 (49): 20842–6. doi:10.1073/pnas.0911267106. PMC 2791563. PMID 19926846.
  9. ↑ 9.0 9.1 Barber GN (February 2011). "Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses". Curr. Opin. Immunol. 23 (1): 10–20. doi:10.1016/j.coi.2010.12.015. PMID 21239155.
  10. ↑ 10.0 10.1 Keating SE, Baran M, Bowie AG (December 2011). "Cytosolic DNA sensors regulating type I interferon induction". Trends Immunol. 32 (12): 574–81. doi:10.1016/j.it.2011.08.004. PMID 21940216.
  11. ↑ 11.0 11.1 Jin L, Getahun A, Knowles HM, Mogan J, Akerlund LJ, Packard TA, Perraud AL, Cambier JC (March 2013). "STING/MPYS mediates host defense against Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration". J. Immunol. 190 (6): 2835–43. doi:10.4049/jimmunol.1201788. PMID 23378430.
  12. ↑ Woodward JJ, Iavarone AT, Portnoy DA (June 2010). "c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response". Science 328 (5986): 1703–5. doi:10.1126/science.1189801. PMC 3156580. PMID 20508090.
  13. ↑ Ishikawa H, Ma Z, Barber GN (October 2009). "STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity". Nature 461 (7265): 788–92. doi:10.1038/nature08476. PMID 19776740.
  14. ↑ 14.0 14.1 Sharma S, DeOliveira RB, Kalantari P et al. (August 2011). "Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome". Immunity 35 (2): 194–207. doi:10.1016/j.immuni.2011.05.016. PMC 3162998. PMID 21820332.
  15. ↑ 15.0 15.1 Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS (May 2012). "Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages". Cell Host Microbe 11 (5): 469–80. doi:10.1016/j.chom.2012.03.007. PMID 22607800.
  16. ↑ Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, Xia W, Gu J, Ishikawa H, Gutman D, Barber G, Qin Z, Jiang Z (October 2011). "Activation of STAT6 by STING is critical for antiviral innate immunity". Cell 147 (2): 436–46. doi:10.1016/j.cell.2011.09.022. PMID 22000020.
  17. ↑ Watson RO, Manzanillo PS, Cox JS (August 2012). "Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway". Cell 150 (4): 803–15. doi:10.1016/j.cell.2012.06.040. PMC 3708656. PMID 22901810.
  18. ↑ McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M, Joncker NT, Ishii KJ, Akira S, Colonna M, Chen ZJ, Fitzgerald KA, Hayakawa Y, Vance RE (August 2009). "A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP". J. Exp. Med. 206 (9): 1899–911. doi:10.1084/jem.20082874. PMC 2737161. PMID 19652017.
  19. ↑ Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (October 2011). "STING is a direct innate immune sensor of cyclic di-GMP". Nature 478 (7370): 515–8. doi:10.1038/nature10429. PMC 3203314. PMID 21947006.
  20. ↑ Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ (October 2011). "The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells". Nat. Immunol. 12 (10): 959–65. doi:10.1038/ni.2091. PMC 3671854. PMID 21892174.
  21. ↑ Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ (February 2013). "Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA". Science 339 (6121): 826–30. doi:10.1126/science.1229963. PMID 23258412.
  22. ↑ Sun L, Wu J, Du F, Chen X, Chen ZJ (February 2013). "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway". Science 339 (6121): 786–91. doi:10.1126/science.1232458. PMID 23258413.