Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC1WUVF)

• DOT Name: Nuclear protein localization protein 4 homolog (NPLOC4)
• Synonyms: Protein NPL4
• Gene Name: NPLOC4
• Related Disease:
  Age-related macular degeneration
  DiGeorge syndrome
  Neovascular age-related macular degeneration
  Ovarian neoplasm
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Myopia
• UniProt ID: NPL4_HUMAN
• PDB ID: 7WWP; 7WWQ
• Pfam ID: PF05021 ; PF11543 ; PF05020
• Sequence:
  MAESIIIRVQSPDGVKRITATKRETAATFLKKVAKEFGFQNNGFSVYINRNKTGEITASS
  NKSLNLLKIKHGDLLFLFPSSLAGPSSEMETSVPPGFKVFGAPNVVEDEIDQYLSKQDGK
  IYRSRDPQLCRHGPLGKCVHCVPLEPFDEDYLNHLEPPVKHMSFHAYIRKLTGGADKGKF
  VALENISCKIKSGCEGHLPWPNGICTKCQPSAITLNRQKYRHVDNIMFENHTVADRFLDF
  WRKTGNQHFGYLYGRYTEHKDIPLGIRAEVAAIYEPPQIGTQNSLELLEDPKAEVVDEIA
  AKLGLRKVGWIFTDLVSEDTRKGTVRYSRNKDTYFLSSEECITAGDFQNKHPNMCRLSPD
  GHFGSKFVTAVATGGPDNQVHFEGYQVSNQCMALVRDECLLPCKDAPELGYAKESSSEQY
  VPDVFYKDVDKFGNEITQLARPLPVEYLIIDITTTFPKDPVYTFSISQNPFPIENRDVLG
  ETQDFHSLATYLSQNTSSVFLDTISDFHLLLFLVTNEVMPLQDSISLLLEAVRTRNEELA
  QTWKRSEQWATIEQLCSTVGGQLPGLHEYGAVGGSTHTATAAMWACQHCTFMNQPGTGHC
  EMCSLPRT
• Function: The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Acts as a negative regulator of type I interferon production via the complex formed with VCP and UFD1, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI.
• Tissue Specificity: Expressed at highest levels in brain, heart, skeletal muscle, kidney and fetal liver.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Translesion Synthesis by POLH (R-HSA-110320)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
DiGeorge syndrome	DIST1RKO	Strong	Genetic Variation	[2]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	moderate	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[4]
Myopia	DISK5S60	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[10]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[12]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Nuclear protein localization protein 4 homolog (NPLOC4).	[13]

References

• [1] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [2] Cloning and characterization of the gene encoding human NPL4, a protein interacting with the ubiquitin fusion-degradation protein (UFD1L).Gene. 2001 Sep 5;275(1):39-46. doi: 10.1016/s0378-1119(01)00649-7.
• [3] Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.Genes Dev. 2008 Feb 15;22(4):528-42. doi: 10.1101/gad.463208.
• [4] Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA.Cancer Cell Int. 2019 May 30;19:149. doi: 10.1186/s12935-019-0874-2. eCollection 2019.
• [5] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.