transmembrane protein 173 | Other pattern recognition receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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transmembrane protein 173

Target id: 2902

Nomenclature: transmembrane protein 173

Abbreviated Name: STING

Family: Other pattern recognition receptors

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     transmembrane protein 173 has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 379 5q31.2 TMEM173 transmembrane protein 173
Mouse 4 379 18 B3 Tmem173 transmembrane protein 173
Rat - 379 18p11 Tmem173 transmembrane protein 173
Gene and Protein Information Comments
For the human and mouse genes alternate splicing is reported to result in multiple transcript variants, and protein isoforms. We provide details for the longest transcripts and proteins here. The Entrez gene links provide full details of other variants identified.
Previous and Unofficial Names
NET23 | STimulator of INterferon Genes | STING
Database Links
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of STING in complex with cGAMP
PDB Id:  4KSY
Ligand:  2'3'-cGAMP
Resolution:  1.88Å
Species:  Human
References:  23

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
2'3'-cGAMP Hs Agonist 8.3 – 8.4 pKd 23
pKd 8.3 – 8.4 (Kd 4.59x10-9 – 3.79x10-9 M) [23]
Immunopharmacology Comments
STING functions as a major regulator of the innate immune response to viral and bacterial infections [17]. Located in the endoplasmic reticulum, it acts as a pattern recognition receptor, activating type I interferon (IFN) responses upon direct binding to a variety of different cyclic-di-nucleotides (for example of pathogenic origin) [2,4,12-13,21]. Mechanistically, STING mediates DNA-induced TANK-binding kinase 1 (TBK1) activation, which in turn coordinates the phosphorylation-induced activation of IRF3 (an interferon regulatory transcription factor (IRF)) leading to transcriptional regulation of immune response genes including type I IFNs and antiviral IFN-stimulated genes [21]. In cancer, STING is reported to mediate immune recognition of immunogenic tumours, by activating the cyclic-GMP-AMP synthase (cGAS)-STING-interferon regulatory factor 3 (IRF3) pathway in response to the detection of tumor-cell-derived DNA [15,22].
STING sits at the crossroads of infection, inflammation and cancer, hence pharmaceutical industry interest is intense [3]. Pharmacological stimulation of innate type I IFN responses by STING agonists is being investigated as a novel way to combat viral infections [11,19], and for immuno-oncology potential [1,5,8-10,18]. Merck have STING agonist MK-1454 in Phase 1 clinical trial in patients with advanced/metastatic solid tumours or lymphomas (NCT03010176). Spring Bank Pharmaceuticals have their STING agonist coded SB 11285 in preclinical development as a potential immuno-oncology agent. Both MK-1454 and SB 11285 are cyclic dinucleotides (i.e. they are endogenous STING agonist mimetics), although their precise chemical structures have not been disclosed (September 2017).

Identification of activating STING mutations as the cause of infantile-onset STING-associated vasculopathy (SAVI) [7,16] has instigated the search for pharmacological inhibitors of STING, as a therapeutic strategy not only for SAVI but also for other DNA-induced type I interferonopathies, including systemic lupus erythematosus [6,14].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0002218 activation of innate immune response IMP
GO:0043312 neutrophil degranulation TAS
GO:0045087 innate immune response IDA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0002218 activation of innate immune response IMP
GO:0002230 positive regulation of defense response to virus by host IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0032479 regulation of type I interferon production TAS
GO:0032481 positive regulation of type I interferon production IDA
GO:0032608 interferon-beta production IDA
click arrow to show/hide IEA associations
GO:0035458 cellular response to interferon-beta IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Physiological Functions
STING mediates synthesis of type I interferon and initiation of immune responses upon detection of aberrant DNA species or cyclic di-GMP-AMP (cGAMP) in the cytosol
Species:  Human
Tissue: 
References:  3
Clinically-Relevant Mutations and Pathophysiology
Disease:  STING-associated vasculopathy with onset in infancy
Description: An autoinflammatory interferonopathy characterised by neonatal-onset of systemic inflammation especially affecting the skin, blood vessels, and lungs.
Synonyms: SAVI
STING-associated vasculopathy, infantile-onset
OMIM: 615934
Drugs: 
References:  16,20
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S102P + F279L p.Ser102Pro is located within the transmembrane region of STING, and p.Phe279Leu is located in the cytoplasmic domain. These domains are believed to be involved in homodimerization and maintenance of proper subcellular localisation. 20
Missense, gain of function Human V147L 16
Missense, gain of function Human N154S 16
Missense, gain of function Human V155M 16

References

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1. Ager CR, Reilley MJ, Nicholas C, Bartkowiak T, Jaiswal AR, Curran MA. (2017) Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity. Cancer Immunol Res, 5 (8): 676-684. [PMID:28674082]

2. Barber GN. (2014) STING-dependent cytosolic DNA sensing pathways. Trends Immunol., 35 (2): 88-93. [PMID:24309426]

3. Barber GN. (2015) STING: infection, inflammation and cancer. Nat. Rev. Immunol., 15 (12): 760-70. [PMID:26603901]

4. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE. (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature, 478 (7370): 515-8. [PMID:21947006]

5. Corrales L, Gajewski TF. (2015) Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer. Clin. Cancer Res., 21 (21): 4774-9. [PMID:26373573]

6. Crow YJ. (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N. Y. Acad. Sci., 1238: 91-8. [PMID:22129056]

7. Crow YJ, Casanova JL. (2014) STING-associated vasculopathy with onset in infancy--a new interferonopathy. N. Engl. J. Med., 371 (6): 568-71. [PMID:25029336]

8. Curran E, Chen X, Corrales L, Kline DE, Dubensky Jr TW, Duttagupta P, Kortylewski M, Kline J. (2016) STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia. Cell Rep, 15 (11): 2357-66. [PMID:27264175]

9. Foote JB, Kok M, Leatherman JM, Armstrong TD, Marcinkowski BC, Ojalvo LS, Kanne DB, Jaffee EM, Dubensky Jr TW, Emens LA. (2017) A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice. Cancer Immunol Res, 5 (6): 468-479. [PMID:28483787]

10. Gadkaree SK, Fu J, Sen R, Korrer MJ, Allen C, Kim YJ. (2017) Induction of tumor regression by intratumoral STING agonists combined with anti-programmed death-L1 blocking antibody in a preclinical squamous cell carcinoma model. Head Neck, 39 (6): 1086-1094. [PMID:28323387]

11. Guo F, Tang L, Shu S, Sehgal M, Sheraz M, Liu B, Zhao Q, Cheng J, Zhao X, Zhou T et al.. (2017) Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus. Antimicrob. Agents Chemother., 61 (10). [PMID:28717041]

12. Ishikawa H, Barber GN. (2011) The STING pathway and regulation of innate immune signaling in response to DNA pathogens. Cell. Mol. Life Sci., 68 (7): 1157-65. [PMID:21161320]

13. Ishikawa H, Ma Z, Barber GN. (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature, 461 (7265): 788-92. [PMID:19776740]

14. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, Goudin N, Frémond ML, Nitschke P, Molina TJ et al.. (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Invest., 124 (12): 5516-20. [PMID:25401470]

15. Larkin B, Ilyukha V, Sorokin M, Buzdin A, Vannier E, Poltorak A. (2017) Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death. J. Immunol., 199 (2): 397-402. [PMID:28615418]

16. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS et al.. (2014) Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med., 371 (6): 507-18. [PMID:25029335]

17. Liu Y, Lin R, Olagnier D. (2017) RIGulation of STING expression: at the crossroads of viral RNA and DNA sensing pathways. Inflamm Cell Signal, 4 (1): e1491. [PMID:28191486]

18. Ohkuri T, Ghosh A, Kosaka A, Sarkar SN, Okada H. (2015) Protective role of STING against gliomagenesis: Rational use of STING agonist in anti-glioma immunotherapy. Oncoimmunology, 4 (4): e999523. [PMID:26137417]

19. Sali TM, Pryke KM, Abraham J, Liu A, Archer I, Broeckel R, Staverosky JA, Smith JL, Al-Shammari A, Amsler L et al.. (2015) Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathog., 11 (12): e1005324. [PMID:26646986]

20. Seo J, Kang JA, Suh DI, Park EB, Lee CR, Choi SA, Kim SY, Kim Y, Park SH, Ye M et al.. (2017) Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. J. Allergy Clin. Immunol., 139 (4): 1396-1399.e12. [PMID:28041677]

21. Tang CH, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, Hu CC. (2016) Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells. Cancer Res., 76 (8): 2137-52. [PMID:26951929]

22. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA et al.. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity, 41 (5): 830-42. [PMID:25517615]

23. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ. (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell, 51 (2): 226-35. [PMID:23747010]

How to cite this page

Other pattern recognition receptors: transmembrane protein 173. Last modified on 16/08/2018. Accessed on 11/12/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2902.