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Identification
HMDB Protein ID HMDBP12692
Secondary Accession Numbers None
Name Stimulator of interferon genes protein
Synonyms
  1. mSTING
  2. Endoplasmic reticulum interferon stimulator
  3. Mediator of IRF3 activation
  4. Transmembrane protein 173
  5. ERIS
  6. MMITA
Gene Name STING1
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:18818105, PubMed:19433799, PubMed:19776740, PubMed:26229117, PubMed:26669264). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (PubMed:18818105, PubMed:19433799, PubMed:19776740, PubMed:26229117, PubMed:26669264). Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol (PubMed:21947006, PubMed:23722158, PubMed:23258412, PubMed:23519410, PubMed:23910378). Upon binding of c-di-GMP or cGAMP, STING1 oligomerizes, translocates from the endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent anti-viral state (PubMed:25636800). In addition to promote the production of type I interferons, plays a direct role in autophagy (PubMed:30568238). Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (By similarity). The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome (By similarity). The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (By similarity). Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (PubMed:29056340). Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263). The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (By similarity). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (By similarity). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (PubMed:18559423).
Pathways
  • Coronavirus disease - COVID-19
  • Cytosolic DNA-sensing pathway
  • Herpes simplex virus 1 infection
  • Human cytomegalovirus infection
  • Human immunodeficiency virus 1 infection
  • NOD-like receptor signaling pathway
  • RIG-I-like receptor signaling pathway
Reactions Not Available
GO Classification
Biological Process
regulation of inflammatory response
activation of innate immune response
autophagosome assembly
cellular response to exogenous dsRNA
regulation of cellular metabolic process
reticulophagy
positive regulation of protein binding
positive regulation of macroautophagy
positive regulation of interferon-beta production
cellular response to interferon-beta
protein oligomerization
cellular response to organic cyclic compound
positive regulation of sequence-specific DNA binding transcription factor activity
defense response to virus
innate immune response
positive regulation of defense response to virus by host
positive regulation of transcription from RNA polymerase II promoter
regulation of gene expression
positive regulation of type I interferon production
Cellular Component
endoplasmic reticulum membrane
cytosol
cytoplasm
endoplasmic reticulum
integral to endoplasmic reticulum membrane
plasma membrane
Golgi apparatus
perinuclear region of cytoplasm
autophagic vacuole membrane
autophagosome
integral component of endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane
nucleoplasm
mitochondrial outer membrane
peroxisome
endosome
Molecular Function
protein kinase binding
cyclic-di-GMP binding
cyclic-GMP-AMP binding
ubiquitin protein ligase binding
transcription factor binding
protein homodimerization activity
identical protein binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 378
Molecular Weight 42829.425
Theoretical pI 7.415
Pfam Domain Function
Signals Not Available
Transmembrane Regions
  • 18-34;45-69;92-106;116-133;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q3TBT3
UniProtKB/Swiss-Prot Entry Name STING_MOUSE
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  3. Ishikawa H, Barber GN: STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008 Oct 2;455(7213):674-8. doi: 10.1038/nature07317. Epub 2008 Aug 24. [PubMed:18724357 ]
  4. Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP: A tissue-specific atlas of mouse protein phosphorylation and expression. Cell. 2010 Dec 23;143(7):1174-89. doi: 10.1016/j.cell.2010.12.001. [PubMed:21183079 ]
  5. Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu HB: The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008 Oct 17;29(4):538-50. doi: 10.1016/j.immuni.2008.09.003. Epub 2008 Sep 25. [PubMed:18818105 ]
  6. Jin L, Waterman PM, Jonscher KR, Short CM, Reisdorph NA, Cambier JC: MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol Cell Biol. 2008 Aug;28(16):5014-26. doi: 10.1128/MCB.00640-08. Epub 2008 Jun 16. [PubMed:18559423 ]
  7. Ishikawa H, Ma Z, Barber GN: STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009 Oct 8;461(7265):788-92. doi: 10.1038/nature08476. Epub 2009 Sep 23. [PubMed:19776740 ]
  8. Sun W, Li Y, Chen L, Chen H, You F, Zhou X, Zhou Y, Zhai Z, Chen D, Jiang Z: ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8653-8. doi: 10.1073/pnas.0900850106. Epub 2009 May 11. [PubMed:19433799 ]
  9. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE: STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011 Sep 25;478(7370):515-8. doi: 10.1038/nature10429. [PubMed:21947006 ]
  10. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V: cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013 Jun 20;498(7454):380-4. doi: 10.1038/nature12306. Epub 2013 May 30. [PubMed:23722158 ]
  11. Kranzusch PJ, Wilson SC, Lee AS, Berger JM, Doudna JA, Vance RE: Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling. Mol Cell. 2015 Sep 17;59(6):891-903. doi: 10.1016/j.molcel.2015.07.022. Epub 2015 Aug 20. [PubMed:26300263 ]
  12. Zhang H, Han MJ, Tao J, Ye ZY, Du XX, Deng MJ, Zhang XY, Li LF, Jiang ZF, Su XD: Rat and human STINGs profile similarly towards anticancer/antiviral compounds. Sci Rep. 2015 Dec 16;5:18035. doi: 10.1038/srep18035. [PubMed:26669264 ]
  13. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, Chen ZJ: Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29. [PubMed:25636800 ]
  14. Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J: Viruses transfer the antiviral second messenger cGAMP between cells. Science. 2015 Sep 11;349(6253):1228-32. doi: 10.1126/science.aab3632. Epub 2015 Jul 30. [PubMed:26229117 ]
  15. Moretti J, Roy S, Bozec D, Martinez J, Chapman JR, Ueberheide B, Lamming DW, Chen ZJ, Horng T, Yeretssian G, Green DR, Blander JM: STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell. 2017 Nov 2;171(4):809-823.e13. doi: 10.1016/j.cell.2017.09.034. Epub 2017 Oct 19. [PubMed:29056340 ]
  16. Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S, Sehgal SA, Wang X, Wang J, Shang Y, Jiang Z, Liu L, Chen Q: STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2019 Sep;26(9):1735-1749. doi: 10.1038/s41418-018-0251-z. Epub 2018 Dec 19. [PubMed:30568238 ]
  17. Wang L, Wen M, Cao X: Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses. Science. 2019 Aug 16;365(6454). pii: science.aav0758. doi: 10.1126/science.aav0758. Epub 2019 Jul 18. [PubMed:31320558 ]
  18. Chin KH, Tu ZL, Su YC, Yu YJ, Chen HC, Lo YC, Chen CP, Barber GN, Chuah ML, Liang ZX, Chou SH: Novel c-di-GMP recognition modes of the mouse innate immune adaptor protein STING. Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):352-66. doi: 10.1107/S0907444912047269. Epub 2013 Feb 16. [PubMed:23519410 ]
  19. Gao P, Ascano M, Zillinger T, Wang W, Dai P, Serganov AA, Gaffney BL, Shuman S, Jones RA, Deng L, Hartmann G, Barchet W, Tuschl T, Patel DJ: Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA. Cell. 2013 Aug 15;154(4):748-62. doi: 10.1016/j.cell.2013.07.023. Epub 2013 Aug 1. [PubMed:23910378 ]