Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSQTK3A)

• DOT Name: E3 ubiquitin-protein ligase TRIM65 (TRIM65)
• Synonyms: EC 2.3.2.27; Tripartite motif-containing protein 65
• Gene Name: TRIM65
• Related Disease:
  Bladder transitional cell carcinoma
  Adult lymphoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Pediatric lymphoma
  Pneumonia
  Pneumonitis
  Advanced cancer
  Psoriasis
• UniProt ID: TRI65_HUMAN
• PDB ID: 7JL0; 7JL2; 7JL4
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF00643 ; PF00097
• Sequence:
  MAAQLLEEKLTCAICLGLYQDPVTLPCGHNFCGACIRDWWDRCGKACPECREPFPDGAEL
  RRNVALSGVLEVVRAGPARDPGPDPGPGPDPAARCPRHGRPLELFCRTEGRCVCSVCTVR
  ECRLHERALLDAERLKREAQLRASLEVTQQQATQAEGQLLELRKQSSQIQNSACILASWV
  SGKFSSLLQALEIQHTTALRSIEVAKTQALAQARDEEQRLRVHLEAVARHGCRIRELLEQ
  VDEQTFLQESQLLQPPGPLGPLTPLQWDEDQQLGDLKQLLSRLCGLLLEEGSHPGAPAKP
  VDLAPVEAPGPLAPVPSTVCPLRRKLWQNYRNLTFDPVSANRHFYLSRQDQQVKHCRQSR
  GPGGPGSFELWQVQCAQSFQAGHHYWEVRASDHSVTLGVSYPQLPRCRLGPHTDNIGRGP
  CSWGLCVQEDSLQAWHNGEAQRLPGVSGRLLGMDLDLASGCLTFYSLEPQTQPLYTFHAL
  FNQPLTPVFWLLEGRTLTLCHQPGAVFPLGPQEEVLS
• Function: E3 ubiquitin ligase that plays a role in several processes including innate immnity, autophagy or inflammation. Negatively regulates miRNAs by modulating the ubiquitination and stability of TNRC6A, a protein involved in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs. This ubiquitination results in the suppressed expression of miR-138-5p leading to increased autophagy. Upon enteroviral infection, promotes 'Lys-63'-mediated ubiquitination activation of IFIH1/MDA5 leading to innate signaling cascade. Mechanistically, selectively recognizes MDA5 filaments that occur on dsRNAs. Plays also a role in limitation of inflammation through different mechanisms. First, promotes 'Lys-48'-mediated ubiquitination of VCAM1 leading to its degradation and limitation of LPS-induced lung inflammation. In addition, negatively regulates inflammasome activation by promoting 'lys48'-linked ubiquitination of NLRP3 which is critical for the inhibition of NLRP3 inflammasome activation in resting macrophages.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Pneumonia	DIS8EF3M	Strong	Biomarker	[7]
Pneumonitis	DIS88E0K	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[12]

8 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 TRIM65 (TRIM65).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase TRIM65 (TRIM65).	[18]

References

• [1] TRIM65 supports bladder urothelial carcinoma cell aggressiveness by promoting ANXA2 ubiquitination and degradation.Cancer Lett. 2018 Oct 28;435:10-22. doi: 10.1016/j.canlet.2018.07.036. Epub 2018 Aug 1.
• [2] TRIM65 is a potential oncogenic protein via ERK1/2 on Jurkat and Raji cells: A therapeutic target in human lymphoma malignancies.Cell Biol Int. 2018 Nov;42(11):1503-1510. doi: 10.1002/cbin.11035. Epub 2018 Sep 11.
• [3] Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation.Oncogene. 2019 Sep;38(37):6429-6444. doi: 10.1038/s41388-019-0891-6. Epub 2019 Jul 22.
• [4] TRIM65 triggers -catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma.J Cell Sci. 2017 Sep 15;130(18):3108-3115. doi: 10.1242/jcs.206623. Epub 2017 Jul 28.
• [5] Combinatory inhibition of TRIM65 and MDM2 in lung cancer cells.Biochem Biophys Res Commun. 2018 Nov 30;506(3):698-702. doi: 10.1016/j.bbrc.2018.10.130. Epub 2018 Oct 27.
• [6] Knockdown of TRIM65 inhibits autophagy and cisplatin resistance in A549/DDP cells by regulating miR-138-5p/ATG7.Cell Death Dis. 2019 Jun 3;10(6):429. doi: 10.1038/s41419-019-1660-8.
• [7] TRIM65 E3 ligase targets VCAM-1 degradation to limit LPS-induced lung inflammation.J Mol Cell Biol. 2020 Apr 24;12(3):190-201. doi: 10.1093/jmcb/mjz077.
• [8] Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.Nat Commun. 2017 May 24;8:15382. doi: 10.1038/ncomms15382.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.