Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA7G1Y1)

• DOT Name: Autoimmune regulator (AIRE)
• Synonyms: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein; APECED protein
• Gene Name: AIRE
• Related Disease:
  Adult lymphoma
  Alopecia areata
  Autoimmune polyendocrine syndrome type 1
  Lymphoma
  Pediatric lymphoma
  Addison disease
  Adrenocortical insufficiency
  Advanced cancer
  Alzheimer disease
  B-cell neoplasm
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Chronic mucocutaneous candidiasis
  Fatty liver disease
  Female hypogonadism
  Graves disease
  Immunodeficiency
  Multiple sclerosis
  Non-alcoholic fatty liver disease
  Obesity
  Osteosarcoma
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Severe combined immunodeficiency
  Sjogren syndrome
  Skin cancer
  Skin neoplasm
  Uveitis
  Autoimmune polyendocrinopathy
  Hypoparathyroidism
  Melanoma
  Myocardial ischemia
  Neoplasm
  Omenn syndrome
  Systemic sclerosis
  Familial isolated hypoparathyroidism due to impaired PTH secretion
  Type-1/2 diabetes
  Alopecia
  Dental enamel hypoplasia
  Hepatitis
  Myocardial infarction
  Peripheral neuropathy
  Rheumatoid arthritis
• UniProt ID: AIRE_HUMAN
• PDB ID: 1XWH; 2KE1; 2KFT; 2LRI
• Pfam ID: PF03172 ; PF00628 ; PF01342
• Sequence:
  MATDAALRRLLRLHRTEIAVAVDSAFPLLHALADHDVVPEDKFQETLHLKEKEGCPQAFH
  ALLSWLLTQDSTAILDFWRVLFKDYNLERYGRLQPILDSFPKDVDLSQPRKGRKPPAVPK
  ALVPPPRLPTKRKASEEARAAAPAALTPRGTASPGSQLKAKPPKKPESSAEQQRLPLGNG
  IQTMSASVQRAVAMSSGDVPGARGAVEGILIQQVFESGGSKKCIQVGGEFYTPSKFEDSG
  SGKNKARSSSGPKPLVRAKGAQGAAPGGGEARLGQQGSVPAPLALPSDPQLHQKNEDECA
  VCRDGGELICCDGCPRAFHLACLSPPLREIPSGTWRCSSCLQATVQEVQPRAEEPRPQEP
  PVETPLPPGLRSAGEEVRGPPGEPLAGMDTTLVYKHLPAPPSAAPLPGLDSSALHPLLCV
  GPEGQQNLAPGARCGVCGDGTDVLRCTHCAAAFHWRCHFPAGTSRPGTGLRCRSCSGDVT
  PAPVEGVLAPSPARLAPGPAKDDTASHEPALHRDDLESLLSEHTFDGILQWAIQSMARPA
  APFPS
• Function: Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA). Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes. Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Mainly expressed by medullary thymic epithelial cells (mTECs), induces the expression of thousands of tissue-restricted proteins, which are presented on major histocompatibility complex class I (MHC-I) and MHC-II molecules to developing T-cells percolating through the thymic medulla. Also induces self-tolerance through other mechanisms such as the regulation of the mTEC differentiation program. Controls the medullary accumulation of thymic dendritic cells and the development of regulatory T-cell through the regulation of XCL1 expression. Regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes. In thimic B-cells, allows the presentation of licensing-dependent endogenous self-anitgen for negative selection. In secondary lymphoid organs, induces functional inactivation of CD4(+) T-cells. Expressed by a distinct bone marrow-derived population, induces self-tolerance through a mechanism that does not require regulatory T-cells and is resitant to innate inflammatory stimuli.
• Tissue Specificity: Widely expressed. Expressed at higher level in thymus (medullary epithelial cells and monocyte-dendritic cells), pancreas, adrenal cortex and testis. Expressed at lower level in the spleen, fetal liver and lymph nodes. In secondary lymphoid organs, expressed in a discrete population of bone marrow-derived toleregenic antigen presenting cells (APCs) called extrathymic AIRE expressing cells (eTAC)(at protein level) . Isoform 2 and isoform 3 seem to be less frequently expressed than isoform 1, if at all.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Primary immunodeficiency (hsa05340)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Biomarker	[1]
Alopecia areata	DIS0XXBJ	Definitive	Genetic Variation	[2]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	Definitive	Autosomal recessive	[3]
Lymphoma	DISN6V4S	Definitive	Biomarker	[1]
Pediatric lymphoma	DIS51BK2	Definitive	Biomarker	[1]
Addison disease	DIS7HNOH	Strong	Genetic Variation	[4]
Adrenocortical insufficiency	DISZ0CPT	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Biomarker	[7]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[8]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Chronic mucocutaneous candidiasis	DISPSGYF	Strong	Genetic Variation	[10]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[11]
Female hypogonadism	DISWASB4	Strong	Genetic Variation	[12]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[13]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[14]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[15]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[11]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[9]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[17]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[18]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[19]
Skin cancer	DISTM18U	Strong	Biomarker	[20]
Skin neoplasm	DIS16DDV	Strong	Altered Expression	[9]
Uveitis	DISV0RYS	Strong	Genetic Variation	[21]
Autoimmune polyendocrinopathy	DISOLDB2	moderate	Biomarker	[22]
Hypoparathyroidism	DISICS0V	moderate	Genetic Variation	[23]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[24]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[25]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Omenn syndrome	DIS2C887	moderate	Altered Expression	[26]
Systemic sclerosis	DISF44L6	moderate	Genetic Variation	[27]
Familial isolated hypoparathyroidism due to impaired PTH secretion	DISASHAN	Supportive	Autosomal dominant	[23]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[28]
Alopecia	DIS37HU4	Limited	Genetic Variation	[2]
Dental enamel hypoplasia	DISN6ZMR	Limited	Biomarker	[29]
Hepatitis	DISXXX35	Limited	Biomarker	[30]
Myocardial infarction	DIS655KI	Limited	Biomarker	[31]
Peripheral neuropathy	DIS7KN5G	Limited	Biomarker	[19]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[32]

3 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 Autoimmune regulator (AIRE).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Autoimmune regulator (AIRE).	[37]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Autoimmune regulator (AIRE).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Autoimmune regulator (AIRE).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Autoimmune regulator (AIRE).	[35]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Autoimmune regulator (AIRE).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Autoimmune regulator (AIRE).	[38]

References

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• [2] Association of Autoimmune Regulator Gene Rs2075876 Variant, but Not Gene Expression with Alopecia Areata in Males: A Case-control Study.Immunol Invest. 2020 Feb;49(1-2):146-165. doi: 10.1080/08820139.2019.1671450. Epub 2019 Oct 11.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1.J Clin Endocrinol Metab. 2017 Sep 1;102(9):3546-3556. doi: 10.1210/jc.2017-00139.
• [5] A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1.Immunogenetics. 2017 Oct;69(10):643-651. doi: 10.1007/s00251-017-0995-5. Epub 2017 May 24.
• [6] AIRE promotes androgen-independent prostate cancer by directly regulating IL-6 and modulating tumor microenvironment.Oncogenesis. 2018 May 25;7(5):43. doi: 10.1038/s41389-018-0053-7.
• [7] Prostaglandin A1 Inhibits the Cognitive Decline of APP/PS1 Transgenic Mice via PPAR/ABCA1-dependent Cholesterol Efflux Mechanisms.Neurotherapeutics. 2019 Apr;16(2):505-522. doi: 10.1007/s13311-018-00704-1.
• [8] Inhibitory effects of PGA1 and TRI on the apoptosis of cardiac microvascular endothelial cells of rats.Exp Ther Med. 2017 Nov;14(5):4288-4292. doi: 10.3892/etm.2017.5079. Epub 2017 Aug 30.
• [9] Clinicopathological and immunohistochemical analysis of autoimmune regulator expression in patients with osteosarcoma.Clin Exp Metastasis. 2018 Oct;35(7):641-648. doi: 10.1007/s10585-018-9928-4. Epub 2018 Aug 18.
• [10] Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1.Front Immunol. 2018 Nov 19;9:2570. doi: 10.3389/fimmu.2018.02570. eCollection 2018.
• [11] Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats.Mol Nutr Food Res. 2018 Apr;62(8):e1700903. doi: 10.1002/mnfr.201700903. Epub 2018 Apr 3.
• [12] Autoimmune oophoritis with multiple molecular targets mitigated by transgenic expression of mater.Endocrinology. 2011 Jun;152(6):2465-73. doi: 10.1210/en.2011-0022. Epub 2011 Mar 29.
• [13] AIRE genetic variants and predisposition to polygenic autoimmune disease: The case of Graves' disease and a systematic literature review.Hum Immunol. 2016 Aug;77(8):643-651. doi: 10.1016/j.humimm.2016.06.002. Epub 2016 Jun 4.
• [14] Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.J Clin Invest. 2016 Apr 1;126(4):1525-37. doi: 10.1172/JCI81894. Epub 2016 Mar 21.
• [15] Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.Nat Commun. 2016 Apr 13;7:11350. doi: 10.1038/ncomms11350.
• [16] A combination of Lactobacillus mali APS1 and dieting improved the efficacy of obesity treatment via manipulating gut microbiome in mice.Sci Rep. 2018 Apr 18;8(1):6153. doi: 10.1038/s41598-018-23844-y.
• [17] Autoimmune regulator: from loss of function to autoimmunity.Genes Immun. 2003 Jan;4(1):12-21. doi: 10.1038/sj.gene.6363929.
• [18] Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome.Blood. 2009 Jul 2;114(1):105-8. doi: 10.1182/blood-2009-03-211029. Epub 2009 May 4.
• [19] Aire-deficient mice provide a model of corneal and lacrimal gland neuropathy in Sjgren's syndrome.PLoS One. 2017 Sep 19;12(9):e0184916. doi: 10.1371/journal.pone.0184916. eCollection 2017.
• [20] Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes.Nat Genet. 2015 Aug;47(8):933-8. doi: 10.1038/ng.3355. Epub 2015 Jul 13.
• [21] Mouse Models of Experimental Autoimmune Uveitis: Comparative Analysis of Adjuvant-Induced vs Spontaneous Models of Uveitis.Curr Mol Med. 2015;15(6):550-7. doi: 10.2174/1566524015666150731100318.
• [22] Autoimmune Polyendocrinopathy.J Clin Endocrinol Metab. 2019 Oct 1;104(10):4769-4782. doi: 10.1210/jc.2019-00602.
• [23] Exome Sequencing Reveals Mutations in AIRE as a Cause of Isolated Hypoparathyroidism. J Clin Endocrinol Metab. 2017 May 1;102(5):1726-1733. doi: 10.1210/jc.2016-3836.
• [24] AIRE polymorphism, melanoma antigen-specific T cell immunity, and susceptibility to melanoma.Oncotarget. 2016 Sep 20;7(38):60872-60884. doi: 10.18632/oncotarget.11506.
• [25] Adiponectin and insulin resistance are related to restenosis and overall new PCI in subjects with normal glucose tolerance: the prospective AIRE Study.Cardiovasc Diabetol. 2019 Mar 4;18(1):24. doi: 10.1186/s12933-019-0826-0.
• [26] Defect of regulatory T cells in patients with Omenn syndrome.J Allergy Clin Immunol. 2010 Jan;125(1):209-16. doi: 10.1016/j.jaci.2009.10.023.
• [27] AIRE gene polymorphisms in systemic sclerosis associated with autoimmune thyroiditis.Clin Immunol. 2007 Jan;122(1):13-7. doi: 10.1016/j.clim.2006.09.013. Epub 2006 Nov 13.
• [28] A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes.Diabetologia. 2018 Apr;61(4):862-869. doi: 10.1007/s00125-018-4551-0. Epub 2018 Feb 7.
• [29] A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.J Clin Endocrinol Metab. 2016 Aug;101(8):2975-83. doi: 10.1210/jc.2016-1821. Epub 2016 Jun 2.
• [30] Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1.Hepatology. 2001 May;33(5):1047-52. doi: 10.1053/jhep.2001.24031.
• [31] Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.FASEB J. 2002 Jul;16(9):1027-40. doi: 10.1096/fj.01-0793com.
• [32] The Rheumatoid Arthritis Risk Gene AIRE Is Induced by Cytokines in Fibroblast-Like Synoviocytes and Augments the Pro-inflammatory Response.Front Immunol. 2019 Jun 18;10:1384. doi: 10.3389/fimmu.2019.01384. eCollection 2019.
• [33] 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.
• [34] 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.
• [35] Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire. Reprod Toxicol. 2017 Oct;73:184-195. doi: 10.1016/j.reprotox.2017.07.023. Epub 2017 Aug 6.
• [36] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [37] 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.
• [38] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [39] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.