Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLCC64B)

• DOT Name: TRAF3-interacting protein 1 (TRAF3IP1)
• Synonyms: Interleukin-13 receptor alpha 1-binding protein 1; Intraflagellar transport protein 54 homolog; Microtubule-interacting protein associated with TRAF3; MIP-T3
• Gene Name: TRAF3IP1
• Related Disease:
  Ciliopathy
  Senior-Loken syndrome 9
  Short-rib thoracic dysplasia 6 with or without polydactyly
  Nephronophthisis
  Senior-Loken syndrome
  Short rib-polydactyly syndrome, Majewski type
• UniProt ID: MIPT3_HUMAN
• PDB ID: 2EQO
• Pfam ID: PF10243 ; PF17749
• Sequence:
  MNAAVVRRTQEALGKVIRRPPLTEKLLSKPPFRYLHDIITEVIRMTGFMKGLYTDAEMKS
  DNVKDKDAKISFLQKAIDVVVMVSGEPLLAKPARIVAGHEPERTNELLQIIGKCCLNKLS
  SDDAVRRVLAGEKGEVKGRASLTSRSQELDNKNVREEESRVHKNTEDRGDAEIKERSTSR
  DRKQKEELKEDRKPREKDKDKEKAKENGGNRHREGERERAKARARPDNERQKDRGNRERD
  RDSERKKETERKSEGGKEKERLRDRDRERDRDKGKDRDRRRVKNGEHSWDLDREKNREHD
  KPEKKSASSGEMSKKLSDGTFKDSKAETETEISTRASKSLTTKTSKRRSKNSVEGRKEDN
  ISAKSLDSIVSGINNEPNQETTTSEIGTKEANINSTSISDDNSASLRCENIQPNPTEKQK
  GDSTSDAEGDAGPAGQDKSEVPETPEIPNELSSNIRRIPRPGSARPAPPRVKRQDSMEAL
  QMDRSGSGKTVSNVITESHNSDNEEDDQFVVEAAPQLSEMSEIEMVTAVELEEEEKHGGL
  VKKILETKKDYEKLQQSPKPGEKERSLFESAWKKEKDIVSKEIEKLRTSIQTLCKSALPL
  GKIMDYIQEDVDAMQNELQMWHSENRQHAEALQQEQRITDCAVEPLKAELAELEQLIKDQ
  QDKICAVKANILKNEEKIQKMVYSINLTSRR
• Function: Plays an inhibitory role on IL13 signaling by binding to IL13RA1. Involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding. Recruits TRAF3 and DISC1 to the microtubules. Involved in kidney development and epithelial morphogenesis. Involved in the regulation of microtubule cytoskeleton organization. Is a negative regulator of microtubule stability, acting through the control of MAP4 levels. Involved in ciliogenesis.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Biomarker	[1]
Senior-Loken syndrome 9	DISUEZRX	Definitive	Autosomal recessive	[1]
Short-rib thoracic dysplasia 6 with or without polydactyly	DISEN8P1	Strong	GermlineCausalMutation	[2]
Nephronophthisis	DISXU4HY	moderate	Genetic Variation	[1]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[1]
Short rib-polydactyly syndrome, Majewski type	DIS0GCAA	Supportive	Autosomal recessive	[2]

6 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 TRAF3-interacting protein 1 (TRAF3IP1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TRAF3-interacting protein 1 (TRAF3IP1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of TRAF3-interacting protein 1 (TRAF3IP1).	[5]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of TRAF3-interacting protein 1 (TRAF3IP1).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of TRAF3-interacting protein 1 (TRAF3IP1).	[8]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of TRAF3-interacting protein 1 (TRAF3IP1).	[10]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of TRAF3-interacting protein 1 (TRAF3IP1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of TRAF3-interacting protein 1 (TRAF3IP1).	[9]

References

• [1] Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nat Commun. 2015 Oct 21;6:8666. doi: 10.1038/ncomms9666.
• [2] Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. doi: 10.1002/humu.23362. Epub 2017 Nov 6.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [7] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [8] 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.
• [9] 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.
• [10] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.