Details of Drug Off-Target (DOT)

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

• DOT Name: Butyrophilin subfamily 3 member A3 (BTN3A3)
• Gene Name: BTN3A3
• Related Disease:
  Hepatitis C virus infection
  Matthew-Wood syndrome
  Neoplasm
  rubella
  Breast cancer
  Breast carcinoma
  Lung squamous cell carcinoma
• UniProt ID: BT3A3_HUMAN
• PDB ID: 4F8T; 5ZZ3; 6J0G; 6J0K; 6J0L
• Pfam ID: PF13765 ; PF00622 ; PF07686
• Sequence:
  MKMASSLAFLLLNFHVSLFLVQLLTPCSAQFSVLGPSGPILAMVGEDADLPCHLFPTMSA
  ETMELRWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNVTASD
  SGKYLCYFQDGDFYEKALVELKVAALGSDLHIEVKGYEDGGIHLECRSTGWYPQPQIKWS
  DTKGENIPAVEAPVVADGVGLYAVAASVIMRGSSGGGVSCIIRNSLLGLEKTASISIADP
  FFRSAQPWIAALAGTLPISLLLLAGASYFLWRQQKEKIALSRETEREREMKEMGYAATEQ
  EISLREKLQEELKWRKIQYMARGEKSLAYHEWKMALFKPADVILDPDTANAILLVSEDQR
  SVQRAEEPRDLPDNPERFEWRYCVLGCENFTSGRHYWEVEVGDRKEWHIGVCSKNVERKK
  GWVKMTPENGYWTMGLTDGNKYRALTEPRTNLKLPEPPRKVGIFLDYETGEISFYNATDG
  SHIYTFPHASFSEPLYPVFRILTLEPTALTICPIPKEVESSPDPDLVPDHSLETPLTPGL
  ANESGEPQAEVTSLLLPAHPGAEVSPSATTNQNHKLQARTEALY
• Function: Plays a role in T-cell responses in the adaptive immune response.
• Tissue Specificity: Detected in peripheral blood mononuclear cells and in T-cells (at protein level). Detected in spleen and lymphocytes.
• Reactome Pathway: Butyrophilin (BTN) family interactions (R-HSA-8851680)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
rubella	DISXUI9P	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Butyrophilin subfamily 3 member A3 (BTN3A3).	[6]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the acetylation of Butyrophilin subfamily 3 member A3 (BTN3A3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Butyrophilin subfamily 3 member A3 (BTN3A3).	[21]

References

• [1] Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection.Genes Immun. 2015 Jul-Aug;16(5):297-300. doi: 10.1038/gene.2015.14. Epub 2015 Apr 30.
• [2] BTN3A is a prognosis marker and a promising target for V9V2 T cells based-immunotherapy in pancreatic ductal adenocarcinoma (PDAC).Oncoimmunology. 2017 Sep 21;7(1):e1372080. doi: 10.1080/2162402X.2017.1372080. eCollection 2017.
• [3] Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination.Hum Genet. 2014 Nov;133(11):1407-17. doi: 10.1007/s00439-014-1471-z. Epub 2014 Aug 7.
• [4] LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3.Cell Res. 2019 May;29(5):365-378. doi: 10.1038/s41422-019-0155-6. Epub 2019 Mar 11.
• [5] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [13] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [14] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [21] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [22] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.