Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGJMGJ9)

• DOT Name: Tax1-binding protein 1 (TAX1BP1)
• Synonyms: TRAF6-binding protein
• Gene Name: TAX1BP1
• Related Disease:
  Head and neck cancer
  Head and neck carcinoma
  Hypospadias
  Neoplasm
  Oral cavity carcinoma
  Ulcerative colitis
  Alzheimer disease
  Human T-lymphotropic virus 1 infectious disease
  Bacterial infection
• UniProt ID: TAXB1_HUMAN
• PDB ID: 2M7Q; 4BMJ; 4NLH; 4Z4K; 4Z4M; 5AAS; 5YT6; 5Z7G
• Pfam ID: PF07888 ; PF17751 ; PF18112
• Sequence:
  MTSFQEVPLQTSNFAHVIFQNVAKSYLPNAHLECHYTLTPYIHPHPKDWVGIFKVGWSTA
  RDYYTFLWSPMPEHYVEGSTVNCVLAFQGYYLPNDDGEFYQFCYVTHKGEIRGASTPFQF
  RASSPVEELLTMEDEGNSDMLVVTTKAGLLELKIEKTMKEKEELLKLIAVLEKETAQLRE
  QVGRMERELNHEKERCDQLQAEQKGLTEVTQSLKMENEEFKKRFSDATSKAHQLEEDIVS
  VTHKAIEKETELDSLKDKLKKAQHEREQLECQLKTEKDEKELYKVHLKNTEIENTKLMSE
  VQTLKNLDGNKESVITHFKEEIGRLQLCLAEKENLQRTFLLTTSSKEDTCFLKEQLRKAE
  EQVQATRQEVVFLAKELSDAVNVRDRTMADLHTARLENEKVKKQLADAVAELKLNAMKKD
  QDKTDTLEHELRREVEDLKLRLQMAADHYKEKFKECQRLQKQINKLSDQSANNNNVFTKK
  TGNQQKVNDASVNTDPATSASTVDVKPSPSAAEADFDIVTKGQVCEMTKEIADKTEKYNK
  CKQLLQDEKAKCNKYADELAKMELKWKEQVKIAENVKLELAEVQDNYKELKRSLENPAER
  KMEGQNSQSPQCFKTCSEQNGYVLTLSNAQPVLQYGNPYASQETRDGADGAFYPDEIQRP
  PVRVPSWGLEDNVVCSQPARNFSRPDGLEDSEDSKEDENVPTAPDPPSQHLRGHGTGFCF
  DSSFDVHKKCPLCELMFPPNYDQSKFEEHVESHWKVCPMCSEQFPPDYDQQVFERHVQTH
  FDQNVLNFD
• Function: Ubiquitin-binding adapter that participates in inflammatory, antiviral and innate immune processes as well as selective autophagy regulation. Plays a key role in the negative regulation of NF-kappa-B and IRF3 signalings by acting as an adapter for the ubiquitin-editing enzyme A20/TNFAIP3 to bind and inactivate its substrates. Disrupts the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKBKE to attenuate 'Lys63'-linked polyubiquitination of TBK1 and thereby IFN-beta production. Recruits also A20/TNFAIP3 to ubiquitinated signaling proteins TRAF6 and RIPK1, leading to their deubiquitination and disruption of IL-1 and TNF-induced NF-kappa-B signaling pathways. Inhibits virus-induced apoptosis by inducing the 'Lys-48'-linked polyubiquitination and degradation of MAVS via recruitment of the E3 ligase ITCH, thereby attenuating MAVS-mediated apoptosis signaling. As a macroautophagy/autophagy receptor, facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis. Upon NBR1 recruitment to the SQSTM1-ubiquitin condensates, acts as the major recruiter of RB1CC1 to these ubiquitin condensates to promote their autophagic degradation. Mediates the autophagic degradation of other substrates including TICAM1.
• Tissue Specificity: Expressed in all tissues tested.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
• Reactome Pathway:
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[1]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[1]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Oral cavity carcinoma	DISZXMVL	Strong	Genetic Variation	[1]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Disputed	Genetic Variation	[5]
Human T-lymphotropic virus 1 infectious disease	DISN5C4M	Disputed	Biomarker	[6]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[7]

10 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 Tax1-binding protein 1 (TAX1BP1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tax1-binding protein 1 (TAX1BP1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Tax1-binding protein 1 (TAX1BP1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tax1-binding protein 1 (TAX1BP1).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Tax1-binding protein 1 (TAX1BP1).	[12]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Tax1-binding protein 1 (TAX1BP1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tax1-binding protein 1 (TAX1BP1).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Tax1-binding protein 1 (TAX1BP1).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Tax1-binding protein 1 (TAX1BP1).	[18]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Tax1-binding protein 1 (TAX1BP1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tax1-binding protein 1 (TAX1BP1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tax1-binding protein 1 (TAX1BP1).	[16]

References

• [1] Analysis of the TAX1BP1 gene in head and neck cancer patients.Braz J Otorhinolaryngol. 2010 Mar-Apr;76(2):193-8. doi: 10.1590/S1808-86942010000200008.
• [2] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [3] Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma.J Hepatol. 2008 Nov;49(5):746-57. doi: 10.1016/j.jhep.2008.06.019. Epub 2008 Jul 9.
• [4] Altered expression of Tumor Necrosis Factor Alpha -Induced Protein 3 correlates with disease severity in Ulcerative Colitis.Sci Rep. 2017 Aug 25;7(1):9420. doi: 10.1038/s41598-017-09796-9.
• [5] The cargo receptor SQSTM1 ameliorates neurofibrillary tangle pathology and spreading through selective targeting of pathological MAPT (microtubule associated protein tau).Autophagy. 2019 Apr;15(4):583-598. doi: 10.1080/15548627.2018.1532258. Epub 2018 Oct 16.
• [6] Immunization of mice with a peptide derived from the HTLV-1 TAX1BP1 protein induces cross-reactive antibodies against aquaporin 4.Autoimmunity. 2015;48(7):453-9. doi: 10.3109/08916934.2015.1070836. Epub 2015 Aug 14.
• [7] LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy.Cell Microbiol. 2019 Apr;21(4):e12981. doi: 10.1111/cmi.12981. Epub 2019 Jan 21.
• [8] 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.
• [9] 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.
• [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] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [13] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [19] The marine toxin okadaic acid induces alterations in the expression level of cancer-related genes in human neuronal cells. Ecotoxicol Environ Saf. 2013 Jun;92:303-11. doi: 10.1016/j.ecoenv.2013.03.009. Epub 2013 Apr 3.