Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDAP4G0)

• DOT Name: Stimulator of interferon genes protein (STING1)
• Synonyms: hSTING; Endoplasmic reticulum interferon stimulator; ERIS; Mediator of IRF3 activation; hMITA; Transmembrane protein 173
• Gene Name: STING1
• Related Disease:
  Breast cancer
  Pulmonary disease
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Autoimmune disease
  Bacterial infection
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Chilblain lupus 1
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Fatty liver disease
  Glioblastoma multiforme
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Inflammatory bowel disease
  Multiple sclerosis
  Myocardial infarction
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  STING-associated vasculopathy with onset in infancy
  Triple negative breast cancer
  Tuberculosis
  Head-neck squamous cell carcinoma
  Influenza
  Leukemia
  Melanoma
  Pulmonary fibrosis
  Familial chilblain lupus
  Adult lymphoma
  Aicardi-Goutieres syndrome
  Breast carcinoma
  Dengue
  Lymphoma
  Pancreatic cancer
  Pediatric lymphoma
  Small-cell lung cancer
  Vascular disease
• UniProt ID: STING_HUMAN
• PDB ID: 4EF4 ; 4EF5 ; 4EMT ; 4EMU ; 4F5D ; 4F5E ; 4F5W ; 4F5Y ; 4F9E ; 4F9G ; 4KSY ; 4LOH ; 4LOI ; 4QXO ; 4QXP ; 4QXQ ; 4QXR ; 5BQX ; 5JEJ ; 6CFF ; 6CY7 ; 6DNK ; 6DXG ; 6DXL ; 6MX0 ; 6MX3 ; 6MXE ; 6NT5 ; 6O8B ; 6O8C ; 6S26 ; 6S27 ; 6S86 ; 6UKM ; 6UKU ; 6UKV ; 6UKW ; 6UKX ; 6UKY ; 6UKZ ; 6UL0 ; 6XF3 ; 6XF4 ; 6XNP ; 6Y99 ; 6YDB ; 6YDZ ; 6YEA ; 6YWA ; 6YWB ; 6Z0Z ; 6Z15 ; 7A90 ; 7KVX ; 7KVZ ; 7KW1 ; 7MHC ; 7OB3 ; 7Q3B ; 7Q85 ; 7R4H ; 7SHO ; 7SHP ; 7SII ; 7SSM ; 7T9U ; 7T9V ; 7X9P ; 7X9Q ; 8A2H ; 8A2I ; 8A2J ; 8A2K ; 8B2J ; 8FLK ; 8FLM ; 8GJX ; 8GSZ ; 8GT6 ; 8IK3 ; 8STH ; 8STI ; 8T5K ; 8T5L
• Pfam ID: PF15009
• Sequence:
  MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLL
  NGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWM
  LALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIR
  TYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVY
  SNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILA
  DAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQE
  PELLISGMEKPLPLRTDFS
• 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). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, cyclic UMP-AMP (2',3'-cUAMP), and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol. Upon binding to c-di-GMP, cUAMP 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. 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. 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. In addition to promote the production of type I interferons, plays a direct role in autophagy. Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). 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. Promotes autophagy by acting as a proton channel that directs proton efflux from the Golgi to facilitate MAP1LC3B/LC3B lipidation. The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation. Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II); (Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein. Such oncoproteins prevent the ability to sense cytosolic DNA.
• Tissue Specificity: Ubiquitously expressed . Expressed in skin endothelial cells, alveolar type 2 pneumocytes, bronchial epithelium and alveolar macrophages .
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  Shigellosis (hsa05131)
  Human cytomegalovirus infection (hsa05163)
  Herpes simplex virus 1 infection (hsa05168)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  STAT6-mediated induction of chemokines (R-HSA-3249367)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Neutrophil degranulation (R-HSA-6798695)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  STING mediated induction of host immune responses (R-HSA-1834941)

Molecular Interaction Atlas (MIA) of This DOT

51 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Pulmonary disease	DIS6060I	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[8]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[8]
Chilblain lupus 1	DISEBS1O	Strong	Genetic Variation	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[13]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
HIV infectious disease	DISO97HC	Strong	Biomarker	[18]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[19]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[20]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[14]
Obesity	DIS47Y1K	Strong	Biomarker	[22]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[24]
STING-associated vasculopathy with onset in infancy	DISP26TZ	Strong	Autosomal dominant	[25]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[26]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[27]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[28]
Influenza	DIS3PNU3	moderate	Biomarker	[29]
Leukemia	DISNAKFL	moderate	Biomarker	[30]
Melanoma	DIS1RRCY	moderate	Biomarker	[31]
Pulmonary fibrosis	DISQKVLA	moderate	Genetic Variation	[32]
Familial chilblain lupus	DISOSPDL	Supportive	Autosomal dominant	[9]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[33]
Aicardi-Goutieres syndrome	DIS1NH4X	Limited	Altered Expression	[34]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[35]
Dengue	DISKH221	Limited	Biomarker	[36]
Lymphoma	DISN6V4S	Limited	Biomarker	[33]
Pancreatic cancer	DISJC981	Limited	Biomarker	[37]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[33]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[38]
Vascular disease	DISVS67S	Limited	Genetic Variation	[39]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Stimulator of interferon genes protein (STING1).	[40]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Stimulator of interferon genes protein (STING1).	[43]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Stimulator of interferon genes protein (STING1).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Stimulator of interferon genes protein (STING1).	[42]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Stimulator of interferon genes protein (STING1).	[44]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Stimulator of interferon genes protein (STING1).	[45]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Stimulator of interferon genes protein (STING1).	[46]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Stimulator of interferon genes protein (STING1).	[47]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Stimulator of interferon genes protein (STING1).	[48]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Stimulator of interferon genes protein (STING1).	[49]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Stimulator of interferon genes protein (STING1).	[50]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Stimulator of interferon genes protein (STING1).	[51]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Stimulator of interferon genes protein (STING1).	[47]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of Stimulator of interferon genes protein (STING1).	[52]

References

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• [23] Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity.Cancer Immunol Res. 2017 Aug;5(8):676-684. doi: 10.1158/2326-6066.CIR-17-0049. Epub 2017 Jul 3.
• [24] Intratumoral STING activations overcome negative impact of cisplatin on antitumor immunity by inflaming tumor microenvironment in squamous cell carcinoma.Biochem Biophys Res Commun. 2020 Feb 5;522(2):408-414. doi: 10.1016/j.bbrc.2019.11.107. Epub 2019 Nov 23.
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