Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOT3HH0)

• DOT Name: Transportin-3 (TNPO3)
• Synonyms: Importin-12; Imp12; Transportin-SR; TRN-SR
• Gene Name: TNPO3
• Related Disease:
  Limb-girdle muscular dystrophy
  Autoimmune disease
  Autosomal dominant limb-girdle muscular dystrophy type 1F
  HIV infectious disease
  Myopathy
  Myositis disease
  Primary biliary cholangitis
  Rheumatoid arthritis
  Sjogren syndrome
  Systemic lupus erythematosus
  Systemic sclerosis
  Muscular dystrophy
  Autism spectrum disorder
  leukaemia
  Leukemia
  Neurodevelopmental disorder
• UniProt ID: TNPO3_HUMAN
• PDB ID: 4C0O; 4C0P; 4C0Q; 4OL0; 6GX9
• Pfam ID: PF08389
• Sequence:
  MEGAKPTLQLVYQAVQALYHDPDPSGKERASFWLGELQRSVHAWEISDQLLQIRQDVESC
  YFAAQTMKMKIQTSFYELPTDSHASLRDSLLTHIQNLKDLSPVIVTQLALAIADLALQMP
  SWKGCVQTLVEKYSNDVTSLPFLLEILTVLPEEVHSRSLRIGANRRTEIIEDLAFYSSTV
  VSLLMTCVEKAGTDEKMLMKVFRCLGSWFNLGVLDSNFMANNKLLALLFEVLQQDKTSSN
  LHEAASDCVCSALYAIENVETNLPLAMQLFQGVLTLETAYHMAVAREDLDKVLNYCRIFT
  ELCETFLEKIVCTPGQGLGDLRTLELLLICAGHPQYEVVEISFNFWYRLGEHLYKTNDEV
  IHGIFKAYIQRLLHALARHCQLEPDHEGVPEETDDFGEFRMRVSDLVKDLIFLIGSMECF
  AQLYSTLKEGNPPWEVTEAVLFIMAAIAKSVDPENNPTLVEVLEGVVRLPETVHTAVRYT
  SIELVGEMSEVVDRNPQFLDPVLGYLMKGLCEKPLASAAAKAIHNICSVCRDHMAQHFNG
  LLEIARSLDSFLLSPEAAVGLLKGTALVLARLPLDKITECLSELCSVQVMALKKLLSQEP
  SNGISSDPTVFLDRLAVIFRHTNPIVENGQTHPCQKVIQEIWPVLSETLNKHRADNRIVE
  RCCRCLRFAVRCVGKGSAALLQPLVTQMVNVYHVHQHSCFLYLGSILVDEYGMEEGCRQG
  LLDMLQALCIPTFQLLEQQNGLQNHPDTVDDLFRLATRFIQRSPVTLLRSQVVIPILQWA
  IASTTLDHRDANCSVMRFLRDLIHTGVANDHEEDFELRKELIGQVMNQLGQQLVSQLLHT
  CCFCLPPYTLPDVAEVLWEIMQVDRPTFCRWLENSLKGLPKETTVGAVTVTHKQLTDFHK
  QVTSAEECKQVCWALRDFTRLFR
• Function: Importin, which transports target proteins into the nucleus. Specifically mediates the nuclear import of splicing factor serine/arginine (SR) proteins, such as RBM4, SFRS1 and SFRS2, by recognizing phosphorylated SR domains. Also mediates the nuclear import of serine/arginine (SR) protein CPSF6, independently of CPSF6 phosphorylation. The nuclear import process is regulated by the small GTPase Ran that partitions between cytoplasm and nucleus in the predominantly GDP- and GTP-bound form, respectively. Importin associates with target cargo proteins in the cytoplasm, and the competitive binding of GTP-bound Ran induces the release of cargos in the nucleus ; (Microbial infection) Involved in immunodeficiency virus (HIV-1) infection by importing the pre-integration complex (PIC) into the nucleus. Required for a nuclear maturation step of HIV-1 prior to integration.
• Tissue Specificity: Expressed in skeletal muscle.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Viral life cycle - HIV-1 (hsa03250)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Limb-girdle muscular dystrophy	DISI9Y1Z	Definitive	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autosomal dominant limb-girdle muscular dystrophy type 1F	DISBXWDP	Strong	Autosomal dominant	[3]
HIV infectious disease	DISO97HC	Strong	Biomarker	[4]
Myopathy	DISOWG27	Strong	Genetic Variation	[5]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[6]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[6]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[9]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[9]
Muscular dystrophy	DISJD6P7	moderate	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[10]
leukaemia	DISS7D1V	Limited	Biomarker	[11]
Leukemia	DISNAKFL	Limited	Biomarker	[11]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transportin-3 (TNPO3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transportin-3 (TNPO3).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transportin-3 (TNPO3).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transportin-3 (TNPO3).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transportin-3 (TNPO3).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Transportin-3 (TNPO3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transportin-3 (TNPO3).	[18]

References

• [1] The mutation of Transportin 3 gene that causes limb girdle muscular dystrophy 1F induces protection against HIV-1 infection.PLoS Pathog. 2019 Aug 29;15(8):e1007958. doi: 10.1371/journal.ppat.1007958. eCollection 2019 Aug.
• [2] The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.Hum Mol Genet. 2015 Jan 15;24(2):582-96. doi: 10.1093/hmg/ddu455. Epub 2014 Sep 8.
• [3] Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain. 2013 May;136(Pt 5):1508-17. doi: 10.1093/brain/awt074. Epub 2013 Mar 29.
• [4] A trojan horse for human immunodeficiency virus.Chem Biol. 2015 Mar 19;22(3):313-4. doi: 10.1016/j.chembiol.2015.03.002.
• [5] A new family with transportinopathy: increased clinical heterogeneity.Ther Adv Neurol Disord. 2019 Jun 9;12:1756286419850433. doi: 10.1177/1756286419850433. eCollection 2019.
• [6] Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.
• [7] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [8] Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjgren's syndrome.Nat Genet. 2013 Nov;45(11):1284-92. doi: 10.1038/ng.2792. Epub 2013 Oct 6.
• [9] An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation.J Invest Dermatol. 2020 Feb;140(2):348-360.e11. doi: 10.1016/j.jid.2019.06.147. Epub 2019 Aug 15.
• [10] Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.Clin Genet. 2020 Feb;97(2):338-346. doi: 10.1111/cge.13665. Epub 2019 Nov 14.
• [11] Interferon-Inducible MicroRNA miR-128 Modulates HIV-1 Replication by Targeting TNPO3 mRNA.J Virol. 2019 Sep 30;93(20):e00364-19. doi: 10.1128/JVI.00364-19. Print 2019 Oct 15.
• [12] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] 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.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.