Details of Drug Off-Target (DOT)

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

DOT Name	E3 ubiquitin-protein ligase TRIM69 (TRIM69)
Synonyms	EC 2.3.2.27; RFP-like domain-containing protein trimless; RING finger protein 36; RING-type E3 ubiquitin transferase TRIM69; Tripartite motif-containing protein 69
Gene Name	TRIM69
Related Disease	Alcoholic hepatitis ( ) Amyloidosis ( ) Atrial fibrillation ( ) Cataract ( ) Coeliac disease ( ) Dengue ( ) Depression ( ) Endophthalmitis ( ) Hepatitis B virus infection ( ) Hepatitis C virus infection ( ) Herpes simplex infection ( ) Influenza ( ) Invasive pulmonary aspergillosis ( ) Metabolic disorder ( ) Non-alcoholic steatohepatitis ( ) Obesity ( ) Pancreatitis ( ) Progressive multifocal leukoencephalopathy ( ) Respiratory syncytial virus infection ( ) Rift valley fever ( ) Uveitis ( ) Van der Woude syndrome ( ) Zika virus infection ( ) Renal fibrosis ( ) Stroke ( ) Amyotrophic lateral sclerosis ( ) High blood pressure ( ) Hyperglycemia ( ) Neoplasm ( ) Pancreatic cancer ( ) Pneumonia ( )
UniProt ID	TRI69_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4NQJ; 6YXE
EC Number	2.3.2.27
Pfam ID	PF13765 ; PF00622 ; PF15227
Sequence	MEVSTNPSSNIDPGDYVEMNDSITHLPSKVVIQDITMELHCPLCNDWFRDPLMLSCGHNF CEACIQDFWRLQAKETFCPECKMLCQYNNCTFNPVLDKLVEKIKKLPLLKGHPQCPEHGE NLKLFSKPDGKLICFQCKDARLSVGQSKEFLQISDAVHFFTEELAIQQGQLETTLKELQT LRNMQKEAIAAHKENKLHLQQHVSMEFLKLHQFLHSKEKDILTELREEGKALNEEMELNL SQLQEQCLLAKDMLVSIQAKTEQQNSFDFLKDITTLLHSLEQGMKVLATRELISRKLNLG QYKGPIQYMVWREMQDTLCPGLSPLTLDPKTAHPNLVLSKSQTSVWHGDIKKIMPDDPER FDSSVAVLGSRGFTSGKWYWEVEVAKKTKWTVGVVRESIIRKGSCPLTPEQGFWLLRLRN QTDLKALDLPSFSLTLTNNLDKVGIYLDYEGGQLSFYNAKTMTHIYTFSNTFMEKLYPYF CPCLNDGGENKEPLHILHPQ
Function	E3 ubiquitin ligase that plays an important role in antiviral immunity by restricting different viral infections including dengue virus or vesicular stomatitis indiana virus. Ubiquitinates viral proteins such as dengue virus NS3 thereby limiting infection. In addition, acts as a key mediator of type I interferon induced microtubule stabilization by directly associating to microtubules independently of its E3 ligase activity. Plays also a role in cataract formation together with TP53. Mechanistically, inhibits UVB-induced cell apoptosis and reactive oxygen species (ROS) production by inducing TP53 ubiquitination. Regulates centrosome dynamics and mitotic progression by ubiquitinating STK3/MST2; leading to its redistribution to the perinuclear cytoskeleton and subsequent phosphorylation by PLK1.
Reactome Pathway	Antigen processing (R-HSA-983168 )

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Alcoholic hepatitis	DISA7SH0	Strong	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[2]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[3]
Cataract	DISUD7SL	Strong	Altered Expression	[4]
Coeliac disease	DISIY60C	Strong	Biomarker	[5]
Dengue	DISKH221	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Endophthalmitis	DISCQV4J	Strong	Biomarker	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[9]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[10]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[11]
Influenza	DIS3PNU3	Strong	Biomarker	[12]
Invasive pulmonary aspergillosis	DISIZ0VJ	Strong	Biomarker	[13]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[14]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[1]
Obesity	DIS47Y1K	Strong	Altered Expression	[15]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[16]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[17]
Respiratory syncytial virus infection	DIS7FWHY	Strong	Biomarker	[18]
Rift valley fever	DISG6CM2	Strong	Genetic Variation	[19]
Uveitis	DISV0RYS	Strong	Biomarker	[8]
Van der Woude syndrome	DISADZS1	Strong	Biomarker	[20]
Zika virus infection	DISQUCTY	Strong	Biomarker	[21]
Renal fibrosis	DISMHI3I	moderate	Biomarker	[22]
Stroke	DISX6UHX	moderate	Biomarker	[23]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[24]
High blood pressure	DISY2OHH	Limited	Biomarker	[25]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[26]
Neoplasm	DISZKGEW	Limited	Biomarker	[27]
Pancreatic cancer	DISJC981	Limited	Biomarker	[28]
Pneumonia	DIS8EF3M	Limited	Biomarker	[29]
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⏷ Show the Full List of 31 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

9 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 E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[33]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[34]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[35]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[38]
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⏷ Show the Full List of 9 Drug(s)

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 decreases the methylation of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase TRIM69 (TRIM69).	[37]
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References

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2	Triggering microglia through toll-like receptor 2 pathway induced interferon expression in cell and animal model of Alzheimer's disease.Neuroreport. 2018 Dec 5;29(17):1456-1462. doi: 10.1097/WNR.0000000000001132.
3	TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis.Biochem Biophys Res Commun. 2015 Aug 14;464(1):100-5. doi: 10.1016/j.bbrc.2015.05.131. Epub 2015 Jun 5.
4	TRIM69 inhibits cataractogenesis by negatively regulating p53.Redox Biol. 2019 Apr;22:101157. doi: 10.1016/j.redox.2019.101157. Epub 2019 Mar 2.
5	Pepsin digest of wheat gliadin fraction increases production of IL-1 via TLR4/MyD88/TRIF/MAPK/NF-B signaling pathway and an NLRP3 inflammasome activation.PLoS One. 2013 Apr 29;8(4):e62426. doi: 10.1371/journal.pone.0062426. Print 2013.
6	Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3.PLoS Pathog. 2018 Aug 24;14(8):e1007287. doi: 10.1371/journal.ppat.1007287. eCollection 2018 Aug.
7	The adapter proteins of TLRs, TRIF and MYD88, are upregulated in depressed individuals.Int J Psychiatry Clin Pract. 2014 Jan;18(1):41-4. doi: 10.3109/13651501.2013.859708. Epub 2013 Nov 22.
8	Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria.Infect Immun. 2015 Oct;83(10):3926-36. doi: 10.1128/IAI.00502-15. Epub 2015 Jul 20.
9	Reduced expression of TRIF in chronic HBV infected Iranian patients.Clin Res Hepatol Gastroenterol. 2013 Nov;37(5):491-5. doi: 10.1016/j.clinre.2012.11.005. Epub 2013 Feb 20.
10	Correction: Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway.PLoS Pathog. 2018 Nov 16;14(11):e1007455. doi: 10.1371/journal.ppat.1007455. eCollection 2018 Nov.
11	Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics.Annu Rev Immunol. 2011;29:447-91. doi: 10.1146/annurev-immunol-030409-101335.
12	Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity.J Virol. 2006 Jul;80(13):6218-24. doi: 10.1128/JVI.00121-06.
13	PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis.J Immunol. 2014 Sep 1;193(5):2340-8. doi: 10.4049/jimmunol.1400814. Epub 2014 Jul 21.
14	Targeting Trim69 alleviates high fat diet (HFD)-induced hippocampal injury in mice by inhibiting apoptosis and inflammation through ASK1 inactivation.Biochem Biophys Res Commun. 2019 Aug 6;515(4):658-664. doi: 10.1016/j.bbrc.2019.05.027. Epub 2019 Jun 6.
15	Toll-like receptor signaling and serum levels of interferon and lipopolysaccharide binding protein are related to abdominal obesity: a case-control study between metabolically healthy and metabolically unhealthy obese individuals.Nutr Res. 2018 Jul;55:11-20. doi: 10.1016/j.nutres.2018.03.014. Epub 2018 Apr 6.
16	MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells.J Exp Med. 2012 Aug 27;209(9):1671-87. doi: 10.1084/jem.20111706. Epub 2012 Aug 20.
17	Forced expression of RNF36 induces cell apoptosis.Exp Cell Res. 2003 Jul 15;287(2):301-13. doi: 10.1016/s0014-4827(03)00110-1.
18	Neutrophil recruitment and activation are differentially dependent on MyD88/TRIF and MAVS signaling during RSV infection.Mucosal Immunol. 2019 Sep;12(5):1244-1255. doi: 10.1038/s41385-019-0190-0. Epub 2019 Jul 29.
19	Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.PLoS Negl Trop Dis. 2015 Mar 10;9(3):e0003584. doi: 10.1371/journal.pntd.0003584. eCollection 2015 Mar.
20	1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment.Front Immunol. 2019 Sep 18;10:2177. doi: 10.3389/fimmu.2019.02177. eCollection 2019.
21	Predominant role of IPS-1 over TRIF adaptor proteins in early innate immune response against Zika virus in mice.J Gen Virol. 2018 Feb;99(2):209-218. doi: 10.1099/jgv.0.000992. Epub 2018 Jan 3.
22	Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney.Matrix Biol. 2018 Aug;68-69:293-317. doi: 10.1016/j.matbio.2017.12.002. Epub 2017 Dec 15.
23	LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury.J Neuroinflammation. 2011 Oct 14;8:140. doi: 10.1186/1742-2094-8-140.
24	Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes.Cell Death Differ. 2018 Dec;25(12):2130-2146. doi: 10.1038/s41418-018-0098-3. Epub 2018 Mar 22.
25	Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways.Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1027-H1038. doi: 10.1152/ajpheart.00697.2018. Epub 2019 Feb 22.
26	Hyperglycemia induces Toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: implications for diabetic retinopathy.J Diabetes Res. 2014;2014:790902. doi: 10.1155/2014/790902. Epub 2014 Dec 31.
27	Mechanisms promoting escape from mitotic stress-induced tumor cell death.Cancer Res. 2014 Jul 15;74(14):3857-69. doi: 10.1158/0008-5472.CAN-13-3398. Epub 2014 May 23.
28	TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia.Brain Behav Immun. 2018 Oct;73:364-374. doi: 10.1016/j.bbi.2018.05.021. Epub 2018 May 28.
29	Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection.J Immunol. 2009 Nov 15;183(10):6629-38. doi: 10.4049/jimmunol.0901033. Epub 2009 Oct 21.
30	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.
31	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.
32	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.
33	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.
34	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.
35	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
36	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.
37	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.
38	From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.