Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYEO4NR)

• DOT Name: Toll-interacting protein (TOLLIP)
• Gene Name: TOLLIP
• Related Disease:
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Coeliac disease
  Colitis
  Common variable immunodeficiency
  Crohn disease
  Depression
  Fatty liver disease
  Hypersensitivity pneumonitis
  Latent tuberculosis infection
  Legionnaires' disease
  Major depressive disorder
  Malaria
  Nervous system disease
  Plasmodium vivax malaria
  Pulmonary tuberculosis
  Tuberculosis
  Ulcerative colitis
  Stroke
  Cutaneous leishmaniasis
  Leishmaniasis
  Leprosy
  Asthma
  Bacterial infection
• UniProt ID: TOLIP_HUMAN
• PDB ID: 1WGL; 2N31
• Pfam ID: PF00168 ; PF02845
• Sequence:
  MATTVSTQRGPVYIGELPQDFLRITPTQQQRQVQLDAQAAQQLQYGGAVGTVGRLNITVV
  QAKLAKNYGMTRMDPYCRLRLGYAVYETPTAHNGAKNPRWNKVIHCTVPPGVDSFYLEIF
  DERAFSMDDRIAWTHITIPESLRQGKVEDKWYSLSGRQGDDKEGMINLVMSYALLPAAMV
  MPPQPVVLMPTVYQQGVGYVPITGMPAVCSPGMVPVALPPAAVNAQPRCSEEDLKAIQDM
  FPNMDQEVIRSVLEAQRGNKDAAINSLLQMGEEP
• Function: Component of the signaling pathway of IL-1 and Toll-like receptors. Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1 phosphorylation and kinase activity. Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates. In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes. Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P).
• KEGG Pathway: Toll-like receptor sig.ling pathway (hsa04620)
• Reactome Pathway:
  Interleukin-1 signaling (R-HSA-9020702)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Coeliac disease	DISIY60C	Strong	Altered Expression	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Common variable immunodeficiency	DISHE7JQ	Strong	Altered Expression	[5]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Altered Expression	[7]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[2]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Genetic Variation	[8]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[9]
Legionnaires' disease	DIS8V4GQ	Strong	Biomarker	[10]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[11]
Malaria	DISQ9Y50	Strong	Genetic Variation	[12]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[1]
Plasmodium vivax malaria	DISPU3H9	Strong	Genetic Variation	[12]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[9]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[9]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[6]
Stroke	DISX6UHX	moderate	Biomarker	[13]
Cutaneous leishmaniasis	DISRK7TS	Disputed	Genetic Variation	[14]
Leishmaniasis	DISABTW7	Disputed	Genetic Variation	[14]
Leprosy	DISAA4UI	Disputed	Biomarker	[15]
Asthma	DISW9QNS	Limited	Altered Expression	[16]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Toll-interacting protein (TOLLIP).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Toll-interacting protein (TOLLIP).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Toll-interacting protein (TOLLIP).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Toll-interacting protein (TOLLIP).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Toll-interacting protein (TOLLIP).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Toll-interacting protein (TOLLIP).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Toll-interacting protein (TOLLIP).	[22]

References

• [1] Toll-interacting protein deficiency promotes neurodegeneration via impeding autophagy completion in high-fat diet-fed ApoE(-/-) mouse model.Brain Behav Immun. 2017 Jan;59:200-210. doi: 10.1016/j.bbi.2016.10.002. Epub 2016 Oct 5.
• [2] Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy.J Am Heart Assoc. 2017 Apr 10;6(4):e004078. doi: 10.1161/JAHA.116.004078.
• [3] Expression of microbiota, Toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.J Pediatr Gastroenterol Nutr. 2012 Jun;54(6):727-32. doi: 10.1097/MPG.0b013e318241cfa8.
• [4] Toll-interacting protein modulates colitis susceptibility in mice.Inflamm Bowel Dis. 2014 Apr;20(4):660-70. doi: 10.1097/MIB.0000000000000006.
• [5] The Profile of Toll-like Receptor 2 (TLR2), TLR4 and Their Cytosolic Downstream Signaling Pathway in Common Variable Immunodeficiency (CVID) Patients.Iran J Allergy Asthma Immunol. 2018 Apr;17(2):188-200.
• [6] Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator-activated receptor gamma?.Clin Exp Immunol. 2016 Mar;183(3):358-68. doi: 10.1111/cei.12732. Epub 2015 Nov 26.
• [7] TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.Brain Behav Immun. 2017 Jan;59:265-272. doi: 10.1016/j.bbi.2016.09.014. Epub 2016 Sep 15.
• [8] The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study.Lancet Respir Med. 2017 Aug;5(8):639-647. doi: 10.1016/S2213-2600(17)30216-3. Epub 2017 Jun 22.
• [9] Evaluation of TLR2, TLR4, and TOLLIP polymorphisms for their role in tuberculosis susceptibility.APMIS. 2018 Jun;126(6):501-508. doi: 10.1111/apm.12855.
• [10] TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia.Mucosal Immunol. 2019 Nov;12(6):1382-1390. doi: 10.1038/s41385-019-0196-7. Epub 2019 Aug 28.
• [11] Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression.Front Cell Neurosci. 2017 Aug 16;11:237. doi: 10.3389/fncel.2017.00237. eCollection 2017.
• [12] TOLLIP gene variant is associated with Plasmodium vivax malaria in the Brazilian Amazon.Malar J. 2017 Mar 13;16(1):116. doi: 10.1186/s12936-017-1754-7.
• [13] Tollip is a critical mediator of cerebral ischaemia-reperfusion injury.J Pathol. 2015 Oct;237(2):249-62. doi: 10.1002/path.4565. Epub 2015 Jun 22.
• [14] Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil.PLoS Negl Trop Dis. 2015 Jun 24;9(6):e0003875. doi: 10.1371/journal.pntd.0003875. eCollection 2015.
• [15] Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist.J Infect Dis. 2016 Apr 1;213(7):1189-97. doi: 10.1093/infdis/jiv570. Epub 2015 Nov 26.
• [16] Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice.J Innate Immun. 2018;10(2):106-118. doi: 10.1159/000485850. Epub 2018 Jan 27.
• [17] Molecular characterization, expression patterns, and functional analysis of toll-interacting protein (Tollip) in Japanese eel Anguilla japonica.Fish Shellfish Immunol. 2019 Jul;90:52-64. doi: 10.1016/j.fsi.2019.04.053. Epub 2019 Apr 20.
• [18] 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.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.