Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFGU8E3)

DOT Name E3 ubiquitin-protein ligase TRIM56 (TRIM56)
Synonyms EC 2.3.2.27; RING finger protein 109; Tripartite motif-containing protein 56
Gene Name TRIM56
Related Disease
Advanced cancer ( )
Epithelial ovarian cancer ( )
Hepatitis C virus infection ( )
Herpes simplex infection ( )
Influenza ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Yellow fever virus infection ( )
Zika virus infection ( )
Neoplasm ( )
Plasma cell myeloma ( )
Breast cancer ( )
Breast carcinoma ( )
UniProt ID
TRI56_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5JW7
EC Number
2.3.2.27
Pfam ID
PF00643 ; PF13445
Sequence
MVSHGSSPSLLEALSSDFLACKICLEQLRAPKTLPCLHTYCQDCLAQLADGGRVRCPECR
ETVPVPPEGVASFKTNFFVNGLLDLVKARACGDLRAGKPACALCPLVGGTSTGGPATARC
LDCADDLCQACADGHRCTRQTHTHRVVDLVGYRAGWYDEEARERQAAQCPQHPGEALRFL
CQPCSQLLCRECRLDPHLDHPCLPLAEAVRARRPGLEGLLAGVDNNLVELEAARRVEKEA
LARLREQAARVGTQVEEAAEGVLRALLAQKQEVLGQLRAHVEAAEEAARERLAELEGREQ
VARAAAAFARRVLSLGREAEILSLEGAIAQRLRQLQGCPWAPGPAPCLLPQLELHPGLLD
KNCHLLRLSFEEQQPQKDGGKDGAGTQGGEESQSRREDEPKTERQGGVQPQAGDGAQTPK
EEKAQTTREEGAQTLEEDRAQTPHEDGGPQPHRGGRPNKKKKFKGRLKSISREPSPALGP
NLDGSGLLPRPIFYCSFPTRMPGDKRSPRITGLCPFGPREILVADEQNRALKRFSLNGDY
KGTVPVPEGCSPCSVAALQSAVAFSASARLYLINPNGEVQWRRALSLSQASHAVAALPSG
DRVAVSVAGHVEVYNMEGSLATRFIPGGKASRGLRALVFLTTSPQGHFVGSDWQQNSVVI
CDGLGQVVGEYKGPGLHGCQPGSVSVDKKGYIFLTLREVNKVVILDPKGSLLGDFLTAYH
GLEKPRVTTMVDGRYLVVSLSNGTIHIFRVRSPDS
Function
E3 ubiquitin-protein ligase that plays a key role in innate antiviral immunity by mediating ubiquitination of CGAS and STING1. In response to pathogen- and host-derived double-stranded DNA (dsDNA), targets STING1 to 'Lys-63'-linked ubiquitination, thereby promoting its homodimerization, a step required for the production of type I interferon IFN-beta. Also mediate monoubiquitination of CGAS, thereby promoting CGAS oligomerization and subsequent activation. Promotes also TNFalpha-induced NF-kappa-B signaling by mediating 'Lys-63'-linked ubiquitination TAK1, leading to enhanced interaction between TAK1 and CHUK/IKKalpha. Independently of its E3 ubiquitin ligase activity, positive regulator of TLR3 signaling. Potentiates extracellular double stranded RNA (dsRNA)-induced expression of IFNB1 and interferon-stimulated genes ISG15, IFIT1/ISG56, CXCL10, OASL and CCL5/RANTES. Promotes establishment of an antiviral state by TLR3 ligand and TLR3-mediated chemokine induction following infection by hepatitis C virus. Acts as a restriction factor of Zika virus through direct interaction with the viral RNA via its C-terminal region.
Tissue Specificity Widely expressed (at protein level).
Reactome Pathway
Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975 )

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Biomarker [1]
Epithelial ovarian cancer DIS56MH2 Strong Altered Expression [2]
Hepatitis C virus infection DISQ0M8R Strong Altered Expression [3]
Herpes simplex infection DISL1SAV Strong Biomarker [4]
Influenza DIS3PNU3 Strong Biomarker [5]
Ovarian cancer DISZJHAP Strong Altered Expression [2]
Ovarian neoplasm DISEAFTY Strong Altered Expression [2]
Yellow fever virus infection DISK0X5T Strong Biomarker [5]
Zika virus infection DISQUCTY Strong Biomarker [6]
Neoplasm DISZKGEW moderate Biomarker [7]
Plasma cell myeloma DIS0DFZ0 Disputed Biomarker [8]
Breast cancer DIS7DPX1 Limited Altered Expression [9]
Breast carcinoma DIS2UE88 Limited Altered Expression [9]
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⏷ Show the Full List of 13 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 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 TRIM56 (TRIM56). [10]
Quercetin DM3NC4M Approved Quercetin increases the phosphorylation of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [14]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [18]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [14]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [14]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [11]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [12]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [13]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [15]
Testosterone DM7HUNW Approved Testosterone increases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [16]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [17]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [19]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of E3 ubiquitin-protein ligase TRIM56 (TRIM56). [20]
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⏷ Show the Full List of 8 Drug(s)

References

1 Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines.Blood. 2011 Aug 18;118(7):e32-9. doi: 10.1182/blood-2010-12-323659. Epub 2011 Jun 17.
2 Poly r(C) Binding Protein 1 Regulates Posttranscriptional Expression of the Ubiquitin Ligase TRIM56 in Ovarian Cancer.IUBMB Life. 2019 Feb;71(2):177-182. doi: 10.1002/iub.1948. Epub 2018 Oct 3.
3 TRIM56 is an essential component of the TLR3 antiviral signaling pathway.J Biol Chem. 2012 Oct 19;287(43):36404-13. doi: 10.1074/jbc.M112.397075. Epub 2012 Sep 4.
4 TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing.Nat Commun. 2018 Feb 9;9(1):613. doi: 10.1038/s41467-018-02936-3.
5 The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis.J Virol. 2016 Apr 14;90(9):4369-4382. doi: 10.1128/JVI.03172-15. Print 2016 May.
6 The E3 ligase TRIM56 is a host restriction factor of Zika virus and depends on its RNA-binding activity but not miRNA regulation, for antiviral function.PLoS Negl Trop Dis. 2019 Jun 28;13(6):e0007537. doi: 10.1371/journal.pntd.0007537. eCollection 2019 Jun.
7 TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling.Yonsei Med J. 2018 Jan;59(1):43-50. doi: 10.3349/ymj.2018.59.1.43.
8 MiR-9 promotes multiple myeloma progression by regulating TRIM56/NF-B pathway.Cell Biol Int. 2019 Nov;43(11):1223-1233. doi: 10.1002/cbin.11104. Epub 2019 Jul 17.
9 Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56.Oncogenesis. 2019 Apr 18;8(5):30. doi: 10.1038/s41389-019-0139-x.
10 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.
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 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
13 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.
14 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
15 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
16 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
17 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
18 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.
19 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.
20 Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.