Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU3ADNG)

• DOT Name: E3 ubiquitin-protein ligase TRIM41 (TRIM41)
• Synonyms: EC 2.3.2.27; RING finger-interacting protein with C kinase; RINCK; Tripartite motif-containing protein 41
• Gene Name: TRIM41
• Related Disease:
  Parkinson disease
  Herpes simplex infection
  Influenza
• UniProt ID: TRI41_HUMAN
• PDB ID: 2EGM
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MAAVAMTPNPVQTLQEEAVCAICLDYFTDPVSIGCGHNFCRVCVTQLWGGEDEEDRDELD
  REEEEEDGEEEEVEAVGAGAGWDTPMRDEDYEGDMEEEVEEEEEGVFWTSGMSRSSWDNM
  DYVWEEEDEEEDLDYYLGDMEEEDLRGEDEEDEEEVLEEVEEEDLDPVTPLPPPPAPRRC
  FTCPQCRKSFPRRSFRPNLQLANMVQVIRQMHPTPGRGSRVTDQGICPKHQEALKLFCEV
  DEEAICVVCRESRSHKQHSVVPLEEVVQEYKAKLQGHVEPLRKHLEAVQKMKAKEERRVT
  ELKSQMKSELAAVASEFGRLTRFLAEEQAGLERRLREMHEAQLGRAGAAASRLAEQAAQL
  SRLLAEAQERSQQGGLRLLQDIKETFNRCEEVQLQPPEVWSPDPCQPHSHDFLTDAIVRK
  MSRMFCQAARVDLTLDPDTAHPALMLSPDRRGVRLAERRQEVADHPKRFSADCCVLGAQG
  FRSGRHYWEVEVGGRRGWAVGAARESTHHKEKVGPGGSSVGSGDASSSRHHHRRRRLHLP
  QQPLLQREVWCVGTNGKRYQAQSSTEQTLLSPSEKPRRFGVYLDYEAGRLGFYNAETLAH
  VHTFSAAFLGERVFPFFRVLSKGTRIKLCP
• Function: E3 ligase that plays essential roles in innate antiviral response. Directly binds to influenza A virus or vesicular stomatitis virus nucleoproteins and targets them for ubiquitination and proteasomal degradation, thereby limiting viral infections. Activates the innate antiviral response by catalyzing monoubiquitination of CGAS, thereby activating CGAS. Also involved in innate antiviral response by mediating 'Lys-63'-linked polyubiquitylation of BCL10 which in turn hubs NEMO for activation of NF-kappa-B and IRF3 pathways. Catalyzes the ubiquitin-mediated degradation of other substrates including protein kinase C, ZSCAN21 or TOP3B suggesting additional roles besides its function in immune response.
• Tissue Specificity: Expressed in multiple tissues with the highest levels in heart and skeletal muscle.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[2]
Influenza	DIS3PNU3	moderate	Altered Expression	[3]

7 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 TRIM41 (TRIM41).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase TRIM41 (TRIM41).	[10]

References

• [1] The E3Ubiquitin Ligases TRIM17 and TRIM41 Modulate -Synuclein Expression by Regulating ZSCAN21.Cell Rep. 2018 Nov 27;25(9):2484-2496.e9. doi: 10.1016/j.celrep.2018.11.002.
• [2] RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses.Cell Biosci. 2018 May 9;8:35. doi: 10.1186/s13578-018-0233-3. eCollection 2018.
• [3] TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection.J Virol. 2018 Jul 31;92(16):e00905-18. doi: 10.1128/JVI.00905-18. Print 2018 Aug 15.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [11] 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.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.