Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJOV0PG)

• DOT Name: E3 ubiquitin-protein ligase TRIM32 (TRIM32)
• Synonyms: EC 2.3.2.27; 72 kDa Tat-interacting protein; RING-type E3 ubiquitin transferase TRIM32; Tripartite motif-containing protein 32; Zinc finger protein HT2A
• Gene Name: TRIM32
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Autosomal recessive limb-girdle muscular dystrophy type 2H
  Bardet-Biedl syndrome 11
  Advanced cancer
  Anaplastic large cell lymphoma
  Atopic dermatitis
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  Autosomal recessive limb-girdle muscular dystrophy type 2E
  Bardet-Biedl syndrome 1
  Becker muscular dystrophy
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Ciliopathy
  Congestive heart failure
  Duchenne muscular dystrophy
  Lafora disease
  Latent tuberculosis infection
  Leukemia
  Limb-girdle muscular dystrophy
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Muscular dystrophy
  Myopathy
  Neoplasm
  Neuroblastoma
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Obesity
  Parkinson disease
  Psoriasis
  Salmonella infection
  Schizophrenia
  Squamous cell carcinoma
  Gastric cancer
  Stomach cancer
  Bardet biedl syndrome
  Cutaneous squamous cell carcinoma
  Polydactyly
  X-linked Emery-Dreifuss muscular dystrophy
  X-linked myopathy with excessive autophagy
• UniProt ID: TRI32_HUMAN
• PDB ID: 2CT2; 5FEY
• EC Number: 2.3.2.27
• Pfam ID: PF01436 ; PF13445
• Sequence:
  MAAAAASHLNLDALREVLECPICMESFTEEQLRPKLLHCGHTICRQCLEKLLASSINGVR
  CPFCSKITRITSLTQLTDNLTVLKIIDTAGLSEAVGLLMCRSCGRRLPRQFCRSCGLVLC
  EPCREADHQPPGHCTLPVKEAAEERRRDFGEKLTRLRELMGELQRRKAALEGVSKDLQAR
  YKAVLQEYGHEERRVQDELARSRKFFTGSLAEVEKSNSQVVEEQSYLLNIAEVQAVSRCD
  YFLAKIKQADVALLEETADEEEPELTASLPRELTLQDVELLKVGHVGPLQIGQAVKKPRT
  VNVEDSWAMEATASAASTSVTFREMDMSPEEVVASPRASPAKQRGPEAASNIQQCLFLKK
  MGAKGSTPGMFNLPVSLYVTSQGEVLVADRGNYRIQVFTRKGFLKEIRRSPSGIDSFVLS
  FLGADLPNLTPLSVAMNCQGLIGVTDSYDNSLKVYTLDGHCVACHRSQLSKPWGITALPS
  GQFVVTDVEGGKLWCFTVDRGSGVVKYSCLCSAVRPKFVTCDAEGTVYFTQGLGLNLENR
  QNEHHLEGGFSIGSVGPDGQLGRQISHFFSENEDFRCIAGMCVDARGDLIVADSSRKEIL
  HFPKGGGYSVLIREGLTCPVGIALTPKGQLLVLDCWDHCIKIYSYHLRRYSTP
• Function: E3 ubiquitin ligase that plays a role in various biological processes including neural stem cell differentiation, innate immunity, inflammatory resonse and autophagy. Plays a role in virus-triggered induction of IFN-beta and TNF-alpha by mediating the ubiquitination of STING1. Mechanistically, targets STING1 for 'Lys-63'-linked ubiquitination which promotes the interaction of STING1 with TBK1. Regulates bacterial clearance and promotes autophagy in Mycobacterium tuberculosis-infected macrophages. Negatively regulates TLR3/4-mediated innate immune and inflammatory response by triggering the autophagic degradation of TICAM1 in an E3 activity-independent manner. Plays an essential role in oxidative stress induced cell death by inducing loss of transmembrane potential and enhancing mitochondrial reactive oxygen species (ROS) production during oxidative stress conditions. Ubiquitinates XIAP and targets it for proteasomal degradation. Ubiquitinates DTNBP1 (dysbindin) and promotes its degradation. May ubiquitinate BBS2. Ubiquitinates PIAS4/PIASY and promotes its degradation in keratinocytes treated with UVB and TNF-alpha. Also acts as a regulator of autophagy by mediating formation of unanchored 'Lys-63'-linked polyubiquitin chains that activate ULK1: interaction with AMBRA1 is required for ULK1 activation. Positively regulates dendritic branching by promoting ubiquitination and subsequent degradation of the epigenetic factor CDYL ; (Microbial infection) May play a significant role in mediating the biological activity of the HIV-1 Tat protein in vivo. Binds specifically to the activation domain of HIV-1 Tat and can also interact with the HIV-2 and EIAV Tat proteins in vivo.
• Tissue Specificity: Spleen, thymus, prostate, testis, ovary, intestine, colon and skeletal muscle.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2H	DISZ100M	Definitive	Autosomal recessive	[2]
Bardet-Biedl syndrome 11	DISQ8309	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[5]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[7]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[8]
Autosomal recessive limb-girdle muscular dystrophy type 2E	DISQH5PB	Strong	Biomarker	[9]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Biomarker	[10]
Becker muscular dystrophy	DIS5IYHL	Strong	Altered Expression	[11]
Breast cancer	DIS7DPX1	Strong	Biomarker	[12]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[12]
Cardiac failure	DISDC067	Strong	Biomarker	[13]
Ciliopathy	DIS10G4I	Strong	Biomarker	[14]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[13]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[11]
Lafora disease	DIS83JHH	Strong	Biomarker	[15]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[16]
Leukemia	DISNAKFL	Strong	Biomarker	[17]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[20]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[18]
Myopathy	DISOWG27	Strong	Genetic Variation	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[17]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[22]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[23]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[24]
Psoriasis	DIS59VMN	Strong	Altered Expression	[6]
Salmonella infection	DISTJ434	Strong	Biomarker	[25]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[26]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[27]
Gastric cancer	DISXGOUK	moderate	Biomarker	[28]
Stomach cancer	DISKIJSX	moderate	Biomarker	[28]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[29]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[30]
Polydactyly	DIS25BMZ	Limited	Biomarker	[3]
X-linked Emery-Dreifuss muscular dystrophy	DISDPMZ3	Limited	Genetic Variation	[31]
X-linked myopathy with excessive autophagy	DIS1AFQH	Limited	Genetic Variation	[31]

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 TRIM32 (TRIM32).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[39]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[36]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[35]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[35]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[35]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[35]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[37]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[40]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase TRIM32 (TRIM32).	[41]

References

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• [2] Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet. 2002 Mar;70(3):663-72. doi: 10.1086/339083. Epub 2002 Jan 29.
• [3] Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6287-92. doi: 10.1073/pnas.0600158103. Epub 2006 Apr 10.
• [4] Overexpression of E3 ubiquitin ligase tripartite motif 32 correlates with a poor prognosis in patients with gastric cancer.Oncol Lett. 2017 May;13(5):3131-3138. doi: 10.3892/ol.2017.5806. Epub 2017 Mar 6.
• [5] Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.Hum Pathol. 2014 Oct;45(10):1995-2005. doi: 10.1016/j.humpath.2014.06.012. Epub 2014 Jun 30.
• [6] Trim32 Deficiency Enhances Th2 Immunity and Predisposes to Features of Atopic Dermatitis.J Invest Dermatol. 2017 Feb;137(2):359-366. doi: 10.1016/j.jid.2016.09.020. Epub 2016 Oct 5.
• [7] Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.Sci Transl Med. 2011 Aug 10;3(95):95ra75. doi: 10.1126/scitranslmed.3002464.
• [8] Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.Cereb Cortex. 2020 May 14;30(5):3240-3258. doi: 10.1093/cercor/bhz306.
• [9] Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G.Am J Med Genet. 1999 Feb 19;82(5):392-8. doi: 10.1002/(sici)1096-8628(19990219)82:5<392::aid-ajmg7>3.0.co;2-0.
• [10] Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H.Hum Mutat. 2008 Feb;29(2):240-7. doi: 10.1002/humu.20633.
• [11] The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy.Lab Invest. 2016 Aug;96(8):862-71. doi: 10.1038/labinvest.2016.63. Epub 2016 Jun 13.
• [12] TRIM32 promotes proliferation and confers chemoresistance to breast cancer cells through activation of the NF-B pathway.J Cancer. 2018 Apr 5;9(8):1349-1356. doi: 10.7150/jca.22390. eCollection 2018.
• [13] Tripartite motif 32 prevents pathological cardiac hypertrophy.Clin Sci (Lond). 2016 May 1;130(10):813-28. doi: 10.1042/CS20150619. Epub 2016 Feb 16.
• [14] Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7.J Biol Chem. 2014 Mar 21;289(12):8390-401. doi: 10.1074/jbc.M113.534024. Epub 2014 Feb 5.
• [15] Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level.BMC Evol Biol. 2011 Jul 28;11:225. doi: 10.1186/1471-2148-11-225.
• [16] Gene expression profiling of the TRIM protein family reveals potential biomarkers for indicating tuberculosis status.Microb Pathog. 2018 Jan;114:385-392. doi: 10.1016/j.micpath.2017.12.008. Epub 2017 Dec 7.
• [17] TRIM32 promotes neural differentiation through retinoic acid receptor-mediated transcription.J Cell Sci. 2011 Oct 15;124(Pt 20):3492-502. doi: 10.1242/jcs.088799. Epub 2011 Oct 7.
• [18] Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H.Cells. 2019 Mar 16;8(3):254. doi: 10.3390/cells8030254.
• [19] Expression and the potential functions of TRIM32 in lung cancer tumorigenesis.J Cell Biochem. 2019 Apr;120(4):5232-5243. doi: 10.1002/jcb.27798. Epub 2018 Oct 30.
• [20] Trim32 suppresses cerebellar development and tumorigenesis by degrading Gli1/sonic hedgehog signaling.Cell Death Differ. 2020 Apr;27(4):1286-1299. doi: 10.1038/s41418-019-0415-5. Epub 2019 Sep 17.
• [21] Altered myogenesis and premature senescence underlie human TRIM32-related myopathy.Acta Neuropathol Commun. 2019 Mar 1;7(1):30. doi: 10.1186/s40478-019-0683-9.
• [22] Expression of the Parkinson's Disease-Associated Gene Alpha-Synuclein is Regulated by the Neuronal Cell Fate Determinant TRIM32.Mol Neurobiol. 2017 Aug;54(6):4257-4270. doi: 10.1007/s12035-016-9989-9. Epub 2016 Jun 23.
• [23] TRIM32 overexpression improves chemoresistance through regulation of mitochondrial function in non-small-cell lung cancers.Onco Targets Ther. 2018 Nov 5;11:7841-7852. doi: 10.2147/OTT.S176689. eCollection 2018.
• [24] Parkinson's Disease-Associated Mutant LRRK2-Mediated Inhibition of miRNA Activity is Antagonized by TRIM32.Mol Neurobiol. 2018 Apr;55(4):3490-3498. doi: 10.1007/s12035-017-0570-y. Epub 2017 May 15.
• [25] SseK3 Is a Salmonella Effector That Binds TRIM32 and Modulates the Host's NF-B Signalling Activity.PLoS One. 2015 Sep 22;10(9):e0138529. doi: 10.1371/journal.pone.0138529. eCollection 2015.
• [26] Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role.Ann N Y Acad Sci. 1998 Dec 15;861:26-30. doi: 10.1111/j.1749-6632.1998.tb10169.x.
• [27] RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties.Carcinogenesis. 2004 Feb;25(2):157-67. doi: 10.1093/carcin/bgh003. Epub 2003 Oct 24.
• [28] TRIM32 promotes cell proliferation and invasion by activating -catenin signalling in gastric cancer.J Cell Mol Med. 2018 Oct;22(10):5020-5028. doi: 10.1111/jcmm.13784. Epub 2018 Aug 5.
• [29] Bardet-Biedl Syndrome Overview. 2003 Jul 14 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [30] Novel initiation genes in squamous cell carcinomagenesis: a role for substrate-specific ubiquitylation in the control of cell survival.Mol Carcinog. 2007 Aug;46(8):585-90. doi: 10.1002/mc.20344.
• [31] Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite.Neuromuscul Disord. 2013 Feb;23(2):133-8. doi: 10.1016/j.nmd.2012.09.010. Epub 2012 Nov 9.
• [32] 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.
• [33] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] 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.
• [36] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [39] 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.
• [40] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [41] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.