Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPCMV24)

• DOT Name: AP-1 complex subunit sigma-3 (AP1S3)
• Synonyms: Adaptor protein complex AP-1 subunit sigma-1C; Adaptor-related protein complex 1 subunit sigma-1C; Clathrin assembly protein complex 1 sigma-1C small chain; Golgi adaptor HA1/AP1 adaptin sigma-1C subunit; Sigma 1C subunit of AP-1 clathrin; Sigma-adaptin 1C; Sigma1C-adaptin
• Gene Name: AP1S3
• Related Disease:
  Advanced cancer
  Dermatitis
  Generalized pustular psoriasis
  Hepatitis C virus infection
  Matthew-Wood syndrome
  Pustular psoriasis
  Skin disease
  Triple negative breast cancer
  Palmoplantar pustulosis
  Psoriasis 14, pustular
  Asthma
  Inflammation
• UniProt ID: AP1S3_HUMAN
• PDB ID: 4HMY; 6CM9; 6CRI; 6D83; 6D84; 6DFF; 7R4H; 7UX3; 8D4C; 8D4D; 8D4E; 8D4F; 8D4G; 8D9R; 8D9S; 8D9T; 8D9U; 8D9V; 8D9W
• Pfam ID: PF01217
• Sequence:
  MIHFILLFSRQGKLRLQKWYITLPDKERKKITREIVQIILSRGHRTSSFVDWKELKLVYK
  RYASLYFCCAIENQDNELLTLEIVHRYVELLDKYFGNVCELDIIFNFEKAYFILDEFIIG
  GEIQETSKKIAVKAIEDSDMLQEVSTVSQTMGER
• Function: Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. Involved in TLR3 trafficking.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Lysosome (hsa04142)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Nef mediated downregulation of MHC class I complex cell surface expression (R-HSA-164940)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Dermatitis	DISY5SZC	Strong	Biomarker	[2]
Generalized pustular psoriasis	DISTSNLR	Strong	Genetic Variation	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[5]
Pustular psoriasis	DISXOG13	Strong	Genetic Variation	[6]
Skin disease	DISDW8R6	Strong	Genetic Variation	[6]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[1]
Palmoplantar pustulosis	DISCNSWD	Supportive	Autosomal dominant	[7]
Psoriasis 14, pustular	DISL2U2O	Supportive	Autosomal recessive	[7]
Asthma	DISW9QNS	Limited	Genetic Variation	[8]
Inflammation	DISJUQ5T	Limited	Biomarker	[9]

13 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 AP-1 complex subunit sigma-3 (AP1S3).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of AP-1 complex subunit sigma-3 (AP1S3).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of AP-1 complex subunit sigma-3 (AP1S3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of AP-1 complex subunit sigma-3 (AP1S3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of AP-1 complex subunit sigma-3 (AP1S3).	[22]

References

• [1] Molecular pathogenesis of triple-negative breast cancer based on microRNA expression signatures: antitumor miR-204-5p targets AP1S3.J Hum Genet. 2018 Dec;63(12):1197-1210. doi: 10.1038/s10038-018-0510-3. Epub 2018 Sep 18.
• [2] AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.J Invest Dermatol. 2016 Nov;136(11):2251-2259. doi: 10.1016/j.jid.2016.06.618. Epub 2016 Jul 5.
• [3] Generalized Pustular Psoriasis: Clinical Management and Update on Autoinflammatory Aspects.Am J Clin Dermatol. 2020 Apr;21(2):227-236. doi: 10.1007/s40257-019-00492-0.
• [4] AP1S3 is required for hepatitis C virus infection by stabilizing E2 protein.Antiviral Res. 2016 Jul;131:26-34. doi: 10.1016/j.antiviral.2016.04.006. Epub 2016 Apr 11.
• [5] Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation.Cancer Sci. 2018 Jun;109(6):2013-2026. doi: 10.1111/cas.13610. Epub 2018 May 22.
• [6] The genetic basis for most patients with pustular skin disease remains elusive.Br J Dermatol. 2018 Mar;178(3):740-748. doi: 10.1111/bjd.15867. Epub 2018 Jan 22.
• [7] AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet. 2014 May 1;94(5):790-7. doi: 10.1016/j.ajhg.2014.04.005.
• [8] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [9] Newly recognized Mendelian disorders with rheumatic manifestations.Curr Opin Rheumatol. 2015 Sep;27(5):511-9. doi: 10.1097/BOR.0000000000000207.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [19] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] 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.