General Information of Drug Off-Target (DOT) (ID: OT6SP1M9)

DOT Name E3 ubiquitin-protein ligase TRIM38 (TRIM38)
Synonyms EC 2.3.2.27; RING finger protein 15; Tripartite motif-containing protein 38; Zinc finger protein RoRet
Gene Name TRIM38
Related Disease
Familial Mediterranean fever ( )
Gout ( )
Lupus ( )
Sjogren syndrome ( )
Systemic lupus erythematosus ( )
UniProt ID
TRI38_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.3.2.27
Pfam ID
PF13765 ; PF00622 ; PF00643 ; PF15227
Sequence
MASTTSTKKMMEEATCSICLSLMTNPVSINCGHSYCHLCITDFFKNPSQKQLRQETFCCP
QCRAPFHMDSLRPNKQLGSLIEALKETDQEMSCEEHGEQFHLFCEDEGQLICWRCERAPQ
HKGHTTALVEDVCQGYKEKLQKAVTKLKQLEDRCTEQKLSTAMRITKWKEKVQIQRQKIR
SDFKNLQCFLHEEEKSYLWRLEKEEQQTLSRLRDYEAGLGLKSNELKSHILELEEKCQGS
AQKLLQNVNDTLSRSWAVKLETSEAVSLELHTMCNVSKLYFDVKKMLRSHQVSVTLDPDT
AHHELILSEDRRQVTRGYTQENQDTSSRRFTAFPCVLGCEGFTSGRRYFEVDVGEGTGWD
LGVCMENVQRGTGMKQEPQSGFWTLRLCKKKGYVALTSPPTSLHLHEQPLLVGIFLDYEA
GVVSFYNGNTGCHIFTFPKASFSDTLRPYFQVYQYSPLFLPPPGD
Function
E3 ubiquitin-protein and E3 SUMO-protein ligase that acts as a regulator of innate immunity. Acts as a negative regulator of type I interferon IFN-beta production by catalyzing 'Lys-48'-linked polyubiquitination of AZI2/NAP1, leading to its degradation. Mediates 'Lys-48'-linked polyubiquitination and proteasomal degradation of the critical TLR adapter TICAM1, inhibiting TLR3-mediated type I interferon signaling. Acts as positive regulator of the cGAS-STING pathway by acting as a E3 SUMO-protein ligase: mediates sumoylation of CGAS and STING, preventing their degradation and thereby activating the innate immune response to DNA virus. Also acts as a negative regulator of NF-kappa-B signaling independently of its E3 protein ligase activity by promoting lysosome-dependent degradation of TAB2 and TAB3 adapters.
Tissue Specificity Ubiquitous.
Reactome Pathway
Interferon gamma signaling (R-HSA-877300 )

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Familial Mediterranean fever DISVP5WP Strong Genetic Variation [1]
Gout DISHC0U7 Strong Genetic Variation [2]
Lupus DISOKJWA Strong Biomarker [3]
Sjogren syndrome DISUBX7H Strong Biomarker [4]
Systemic lupus erythematosus DISI1SZ7 Strong Biomarker [5]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
27 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 TRIM38 (TRIM38). [6]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [7]
Tretinoin DM49DUI Approved Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [8]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [11]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Quercetin DM3NC4M Approved Quercetin increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [13]
Temozolomide DMKECZD Approved Temozolomide increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [14]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [15]
Testosterone DM7HUNW Approved Testosterone decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [16]
Marinol DM70IK5 Approved Marinol increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [17]
Selenium DM25CGV Approved Selenium decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [18]
Panobinostat DM58WKG Approved Panobinostat increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [19]
Troglitazone DM3VFPD Approved Troglitazone increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [20]
Etoposide DMNH3PG Approved Etoposide decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [21]
Mitomycin DMH0ZJE Approved Mitomycin decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Colchicine DM2POTE Approved Colchicine decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Hydroxyurea DMOQVU9 Approved Hydroxyurea decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Adenine DMZLHKJ Approved Adenine decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [12]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [22]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [18]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [7]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [23]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [26]
crotylaldehyde DMTWRQI Investigative crotylaldehyde decreases the expression of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [27]
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⏷ Show the Full List of 27 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [24]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase TRIM38 (TRIM38). [25]
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References

1 Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell. 1997 Aug 22;90(4):797-807. doi: 10.1016/s0092-8674(00)80539-5.
2 Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
3 A 1.1-Mb transcript map of the hereditary hemochromatosis locus.Genome Res. 1997 May;7(5):441-56. doi: 10.1101/gr.7.5.441.
4 Autoantibodies against the Immunoglobulin-Binding Region of Ro52 Link its Autoantigenicity with Pathogen Neutralization.Sci Rep. 2018 Feb 20;8(1):3345. doi: 10.1038/s41598-018-21522-7.
5 The 52 000 MW Ro/SS-A autoantigen in Sjgren's syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures.Immunology. 2002 Jun;106(2):246-56. doi: 10.1046/j.1365-2567.2002.01417.x.
6 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
7 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
8 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
9 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.
10 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.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
13 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.
14 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.
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 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.
17 Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood. 2005 Feb 1;105(3):1214-21. doi: 10.1182/blood-2004-03-1182. Epub 2004 Sep 28.
18 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
19 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.
20 Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
21 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
22 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
23 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
24 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.
25 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.
26 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.
27 Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.