Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT94GFIF)

• DOT Name: Charged multivesicular body protein 6 (CHMP6)
• Synonyms: Chromatin-modifying protein 6; Vacuolar protein sorting-associated protein 20; Vps20; hVps20
• Gene Name: CHMP6
• Related Disease: Frontotemporal dementia
• UniProt ID: CHMP6_HUMAN
• PDB ID: 2K3W; 3HTU
• Pfam ID: PF03357
• Sequence:
  MGNLFGRKKQSRVTEQDKAILQLKQQRDKLRQYQKRIAQQLERERALARQLLRDGRKERA
  KLLLKKKRYQEQLLDRTENQISSLEAMVQSIEFTQIEMKVMEGLQFGNECLNKMHQVMSI
  EEVERILDETQEAVEYQRQIDELLAGSFTQEDEDAILEELSAITQEQIELPEVPSEPLPE
  KIPENVPVKARPRQAELVAAS
• Function: Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. In the ESCRT-III complex, it probably serves as an acceptor for the ESCRT-II complex on endosomal membranes.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Pyroptosis (R-HSA-5620971)
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)
  HCMV Late Events (R-HSA-9610379)
  Late endosomal microautophagy (R-HSA-9615710)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9679504)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9694676)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia	DISKYHXL	moderate	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Charged multivesicular body protein 6 (CHMP6).	[2]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Charged multivesicular body protein 6 (CHMP6).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Charged multivesicular body protein 6 (CHMP6).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Charged multivesicular body protein 6 (CHMP6).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Charged multivesicular body protein 6 (CHMP6).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Charged multivesicular body protein 6 (CHMP6).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Charged multivesicular body protein 6 (CHMP6).	[7]

References

• [1] Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.J Biol Chem. 2019 Dec 13;294(50):18952-18966. doi: 10.1074/jbc.RA119.009432. Epub 2019 Oct 2.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [5] 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.
• [6] 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.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [8] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.