Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRQA2AI)

• DOT Name: Vacuolar-sorting protein SNF8 (SNF8)
• Synonyms: ELL-associated protein of 30 kDa; ESCRT-II complex subunit VPS22; hVps22
• Gene Name: SNF8
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Hepatitis C virus infection
  leukaemia
  Leukemia
  Neurofibroma
  Neurofibromatosis
• UniProt ID: SNF8_HUMAN
• PDB ID: 2ZME; 3CUQ
• Pfam ID: PF04157
• Sequence:
  MHRRGVGAGAIAKKKLAEAKYKERGTVLAEDQLAQMSKQLDMFKTNLEEFASKHKQEIRK
  NPEFRVQFQDMCATIGVDPLASGKGFWSEMLGVGDFYYELGVQIIEVCLALKHRNGGLIT
  LEELHQQVLKGRGKFAQDVSQDDLIRAIKKLKALGTGFGIIPVGGTYLIQSVPAELNMDH
  TVVLQLAEKNGYVTVSEIKASLKWETERARQVLEHLLKEGLAWLDLQAPGEAHYWLPALF
  TDLYSQEITAEEAREALP
• Function: Component of the endosomal sorting complex required for transport II (ESCRT-II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. The ESCRT-II complex may also play a role in transcription regulation by participating in derepression of transcription by RNA polymerase II, possibly via its interaction with ELL. Required for degradation of both endocytosed EGF and EGFR, but not for the EGFR ligand-mediated internalization. It is also required for the degradation of CXCR4. Required for the exosomal release of SDCBP, CD63 and syndecan.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  HCMV Late Events (R-HSA-9610379)
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Biomarker	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[4]
Neurofibroma	DISIJJMH	Strong	Genetic Variation	[5]
Neurofibromatosis	DIS5N2R6	Strong	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Vacuolar-sorting protein SNF8 (SNF8).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vacuolar-sorting protein SNF8 (SNF8).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Vacuolar-sorting protein SNF8 (SNF8).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Vacuolar-sorting protein SNF8 (SNF8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Vacuolar-sorting protein SNF8 (SNF8).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Vacuolar-sorting protein SNF8 (SNF8).	[9]

References

• [1] The fission yeast homolog of the human transcription factor EAP30 blocks meiotic spindle pole body amplification.Dev Cell. 2005 Jul;9(1):63-73. doi: 10.1016/j.devcel.2005.04.016.
• [2] Identification of CAD candidate genes in GWAS loci and their expression in vascular cells.J Lipid Res. 2013 Jul;54(7):1894-905. doi: 10.1194/jlr.M037085. Epub 2013 May 10.
• [3] Pivotal role for the ESCRT-II complex subunit EAP30/SNF8 in IRF3-dependent innate antiviral defense.PLoS Pathog. 2017 Oct 30;13(10):e1006713. doi: 10.1371/journal.ppat.1006713. eCollection 2017 Oct.
• [4] Cloning and characterization of the EAP30 subunit of the ELL complex that confers derepression of transcription by RNA polymerase II.J Biol Chem. 1999 Jul 30;274(31):21981-5. doi: 10.1074/jbc.274.31.21981.
• [5] The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features.Clin Genet. 2015 May;87(5):401-10. doi: 10.1111/cge.12498. Epub 2014 Nov 22.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.