Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase TRIM4 (TRIM4)
• Synonyms: EC 2.3.2.27; RING finger protein 87; RING-type E3 ubiquitin transferase TRIM4; Tripartite motif-containing protein 4
• Gene Name: TRIM4
• Related Disease:
  Latent tuberculosis infection
  Non-small-cell lung cancer
  Tuberculosis
• UniProt ID: TRIM4_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF00643 ; PF15227
• Sequence:
  MEAEDIQEELTCPICLDYFQDPVSIECGHNFCRGCLHRNWAPGGGPFPCPECRHPSAPAA
  LRPNWALARLTEKTQRRRLGPVPPGLCGRHWEPLRLFCEDDQRPVCLVCRESQEHQTHAM
  APIDEAFESYRTGNFDIHVDEWKRRLIRLLLYHFKQEEKLLKSQRNLVAKMKKVMHLQDV
  EVKNATQWKDKIKSQRMRISTEFSKLHNFLVEEEDLFLQRLNKEEEETKKKLNENTLKLN
  QTIASLKKLILEVGEKSQAPTLELLQNPKEVLTRSEIQDVNYSLEAVKVKTVCQIPLMKE
  MLKRFQVAVNLAEDTAHPKLVFSQEGRYVKNTASASSWPVFSSAWNYFAGWRNPQKTAFV
  ERFQHLPCVLGKNVFTSGKHYWEVESRDSLEVAVGVCREDVMGITDRSKMSPDVGIWAIY
  WSAAGYWPLIGFPGTPTQQEPALHRVGVYLDRGTGNVSFYSAVDGVHLHTFSCSSVSRLR
  PFFWLSPLASLVIPPVTDRK
• Function: E3 ubiquitin-protein ligase. Mediates 'Lys-63'-linked polyubiquitination of the innate immune receptor RIGI, this linkage doesn't lead to proteasomal degradation but seems to enhance IFN induction.
• Reactome Pathway:
  Ovarian tumor domain proteases (R-HSA-5689896)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen processing (R-HSA-983168)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of E3 ubiquitin-protein ligase TRIM4 (TRIM4).	[11]

References

• [1] Gene expression profiling of the TRIM protein family reveals potential biomarkers for indicating tuberculosis status.Microb Pathog. 2018 Jan;114:385-392. doi: 10.1016/j.micpath.2017.12.008. Epub 2017 Dec 7.
• [2] TRIM59 Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer Cells by Upregulating Cell Cycle Related Proteins.PLoS One. 2015 Nov 24;10(11):e0142596. doi: 10.1371/journal.pone.0142596. eCollection 2015.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] 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.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] 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.
• [12] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [13] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [14] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.