Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDDK2SY)

• DOT Name: DnaJ homolog subfamily B member 11 (DNAJB11)
• Synonyms: APOBEC1-binding protein 2; ABBP-2; DnaJ protein homolog 9; ER-associated DNAJ; ER-associated Hsp40 co-chaperone; Endoplasmic reticulum DNA J domain-containing protein 3; ER-resident protein ERdj3; ERdj3; ERj3p; HEDJ; Human DnaJ protein 9; hDj-9; PWP1-interacting protein 4
• Gene Name: DNAJB11
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Alpha-1 antitrypsin deficiency
  Chronic renal failure
  End-stage renal disease
  Gaucher disease
  Interstitial nephritis
  Polycystic kidney disease
  Polycystic kidney disease 6 with or without polycystic liver disease
  Ciliopathy
  Hepatocellular carcinoma
  Liver cirrhosis
  Neoplasm
• UniProt ID: DJB11_HUMAN
• Pfam ID: PF00226 ; PF01556
• Sequence:
  MAPQNLSTFCLLLLYLIGAVIAGRDFYKILGVPRSASIKDIKKAYRKLALQLHPDRNPDD
  PQAQEKFQDLGAAYEVLSDSEKRKQYDTYGEEGLKDGHQSSHGDIFSHFFGDFGFMFGGT
  PRQQDRNIPRGSDIIVDLEVTLEEVYAGNFVEVVRNKPVARQAPGKRKCNCRQEMRTTQL
  GPGRFQMTQEVVCDECPNVKLVNEERTLEVEIEPGVRDGMEYPFIGEGEPHVDGEPGDLR
  FRIKVVKHPIFERRGDDLYTNVTISLVESLVGFEMDITHLDGHKVHISRDKITRPGAKLW
  KKGEGLPNFDNNNIKGSLIITFDVDFPKEQLTEEAREGIKQLLKQGSVQKVYNGLQGY
• Function: As a co-chaperone for HSPA5 it is required for proper folding, trafficking or degradation of proteins. Binds directly to both unfolded proteins that are substrates for ERAD and nascent unfolded peptide chains, but dissociates from the HSPA5-unfolded protein complex before folding is completed. May help recruiting HSPA5 and other chaperones to the substrate. Stimulates HSPA5 ATPase activity. It is necessary for maturation and correct trafficking of PKD1.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Autosomal dominant	[1]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Biomarker	[2]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[3]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[3]
Gaucher disease	DISTW5JG	Strong	Genetic Variation	[4]
Interstitial nephritis	DISKQGND	Strong	Biomarker	[3]
Polycystic kidney disease	DISWS3UY	Strong	Biomarker	[3]
Polycystic kidney disease 6 with or without polycystic liver disease	DISQKHXX	Strong	Autosomal dominant	[5]
Ciliopathy	DIS10G4I	Limited	Autosomal recessive	[1]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Limited	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]

1 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 DnaJ homolog subfamily B member 11 (DNAJB11).	[7]

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 DnaJ homolog subfamily B member 11 (DNAJB11).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[15]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[14]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DnaJ homolog subfamily B member 11 (DNAJB11).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Erdj3 Has an Essential Role for Z Variant Alpha-1-Antitrypsin Degradation.J Cell Biochem. 2017 Oct;118(10):3090-3101. doi: 10.1002/jcb.26069. Epub 2017 Jun 20.
• [3] Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am J Hum Genet. 2018 May 3;102(5):832-844. doi: 10.1016/j.ajhg.2018.03.013. Epub 2018 Apr 26.
• [4] ERdj3 is an endoplasmic reticulum degradation factor for mutant glucocerebrosidase variants linked to Gaucher's disease.Chem Biol. 2014 Aug 14;21(8):967-76. doi: 10.1016/j.chembiol.2014.06.008.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] The endoplasmic reticulum co-chaperone ERdj3/DNAJB11 promotes hepatocellular carcinoma progression through suppressing AATZ degradation.Future Oncol. 2018 Dec;14(29):3001-3013. doi: 10.2217/fon-2018-0401. Epub 2018 Jul 11.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [18] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [19] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.