Details of Drug Off-Target (DOT)

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

DOT Name MHC class II transactivator (CIITA)
Synonyms CIITA; EC 2.3.1.-; EC 2.7.11.1
Gene Name CIITA
Related Disease
Acute myelogenous leukaemia ( )
Classic Hodgkin lymphoma ( )
MHC class II deficiency ( )
Acute coronary syndrome ( )
Addison disease ( )
Arthritis ( )
Asthma ( )
Astrocytoma ( )
B-cell lymphoma ( )
Behcet disease ( )
Choriocarcinoma ( )
Clear cell renal carcinoma ( )
Coeliac disease ( )
Digestive system neuroendocrine tumor, grade 1/2 ( )
Fanconi's anemia ( )
Haematological malignancy ( )
Hepatitis B virus infection ( )
Immunodeficiency ( )
Inflammatory bowel disease ( )
Juvenile idiopathic arthritis ( )
Lupus ( )
Mediastinal large B-cell lymphoma ( )
Myocardial infarction ( )
Nasal polyp ( )
Neoplasm ( )
Osteoporosis ( )
Plasma cell myeloma ( )
Sarcoidosis ( )
Squamous cell carcinoma ( )
Systemic lupus erythematosus ( )
Type-1 diabetes ( )
Uveal Melanoma ( )
Vitiligo ( )
Chronic hepatitis B virus infection ( )
Inflammation ( )
Rhabdomyosarcoma ( )
Advanced cancer ( )
B-cell neoplasm ( )
Glioma ( )
Lymphoma ( )
Melanoma ( )
Nasopharyngeal carcinoma ( )
Nervous system inflammation ( )
UniProt ID
C2TA_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
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EC Number
2.3.1.-; 2.7.11.1
Pfam ID
PF13516 ; PF05729
Sequence
MRCLAPRPAGSYLSEPQGSSQCATMELGPLEGGYLELLNSDADPLCLYHFYDQMDLAGEE
EIELYSEPDTDTINCDQFSRLLCDMEGDEETREAYANIAELDQYVFQDSQLEGLSKDIFK
HIGPDEVIGESMEMPAEVGQKSQKRPFPEELPADLKHWKPAEPPTVVTGSLLVRPVSDCS
TLPCLPLPALFNQEPASGQMRLEKTDQIPMPFSSSSLSCLNLPEGPIQFVPTISTLPHGL
WQISEAGTGVSSIFIYHGEVPQASQVPPPSGFTVHGLPTSPDRPGSTSPFAPSATDLPSM
PEPALTSRANMTEHKTSPTQCPAAGEVSNKLPKWPEPVEQFYRSLQDTYGAEPAGPDGIL
VEVDLVQARLERSSSKSLERELATPDWAERQLAQGGLAEVLLAAKEHRRPRETRVIAVLG
KAGQGKSYWAGAVSRAWACGRLPQYDFVFSVPCHCLNRPGDAYGLQDLLFSLGPQPLVAA
DEVFSHILKRPDRVLLILDGFEELEAQDGFLHSTCGPAPAEPCSLRGLLAGLFQKKLLRG
CTLLLTARPRGRLVQSLSKADALFELSGFSMEQAQAYVMRYFESSGMTEHQDRALTLLRD
RPLLLSHSHSPTLCRAVCQLSEALLELGEDAKLPSTLTGLYVGLLGRAALDSPPGALAEL
AKLAWELGRRHQSTLQEDQFPSADVRTWAMAKGLVQHPPRAAESELAFPSFLLQCFLGAL
WLALSGEIKDKELPQYLALTPRKKRPYDNWLEGVPRFLAGLIFQPPARCLGALLGPSAAA
SVDRKQKVLARYLKRLQPGTLRARQLLELLHCAHEAEEAGIWQHVVQELPGRLSFLGTRL
TPPDAHVLGKALEAAGQDFSLDLRSTGICPSGLGSLVGLSCVTRFRAALSDTVALWESLQ
QHGETKLLQAAEEKFTIEPFKAKSLKDVEDLGKLVQTQRTRSSSEDTAGELPAVRDLKKL
EFALGPVSGPQAFPKLVRILTAFSSLQHLDLDALSENKIGDEGVSQLSATFPQLKSLETL
NLSQNNITDLGAYKLAEALPSLAASLLRLSLYNNCICDVGAESLARVLPDMVSLRVMDVQ
YNKFTAAGAQQLAASLRRCPHVETLAMWTPTIPFSVQEHLQQQDSRISLR
Function
Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter. Does not bind DNA. May act in a coactivator-like fashion through protein-protein interactions by contacting factors binding to the proximal MHC class II promoter, to elements of the transcription machinery, or both PubMed:8402893, PubMed:7749984,. Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter. Also mediates enhanced MHC class I transcription; the promoter element requirements for CIITA-mediated transcription are distinct from those of constitutive MHC class I transcription, and CIITA can functionally replace TAF1 at these genes. Activates CD74 transcription. Exhibits intrinsic GTP-stimulated acetyltransferase activity. Exhibits serine/threonine protein kinase activity: can phosphorylate the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF, histone H2B at 'Ser-37' and other histones (in vitro). Has antiviral activity against Ebola virus and coronaviruses, including SARS-CoV-2. Induces resistance by up-regulation of the p41 isoform of CD74, which blocks cathepsin-mediated cleavage of viral glycoproteins, thereby preventing viral fusion ; [Isoform 3]: Exhibits dominant-negative suppression of MHC class II gene expression.
KEGG Pathway
Antigen processing and presentation (hsa04612 )
Toxoplasmosis (hsa05145 )
Tuberculosis (hsa05152 )
Influenza A (hsa05164 )
Primary immunodeficiency (hsa05340 )
Reactome Pathway
Interferon gamma signaling (R-HSA-877300 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Acute myelogenous leukaemia DISCSPTN Definitive Altered Expression [1]
Classic Hodgkin lymphoma DISV1LU6 Definitive Altered Expression [1]
MHC class II deficiency DISWMI0G Definitive Autosomal recessive [2]
Acute coronary syndrome DIS7DYEW Strong Biomarker [3]
Addison disease DIS7HNOH Strong Genetic Variation [4]
Arthritis DIST1YEL Strong Altered Expression [5]
Asthma DISW9QNS Strong Biomarker [6]
Astrocytoma DISL3V18 Strong Altered Expression [7]
B-cell lymphoma DISIH1YQ Strong Genetic Variation [8]
Behcet disease DISSYMBS Strong Biomarker [9]
Choriocarcinoma DISDBVNL Strong Biomarker [10]
Clear cell renal carcinoma DISBXRFJ Strong Biomarker [11]
Coeliac disease DISIY60C Strong Genetic Variation [12]
Digestive system neuroendocrine tumor, grade 1/2 DISDR98B Strong Biomarker [13]
Fanconi's anemia DISGW6Q8 Strong Altered Expression [14]
Haematological malignancy DISCDP7W Strong Biomarker [15]
Hepatitis B virus infection DISLQ2XY Strong Genetic Variation [16]
Immunodeficiency DIS093I0 Strong Biomarker [17]
Inflammatory bowel disease DISGN23E Strong Genetic Variation [18]
Juvenile idiopathic arthritis DISQZGBV Strong Biomarker [19]
Lupus DISOKJWA Strong Altered Expression [20]
Mediastinal large B-cell lymphoma DISAUA10 Strong Biomarker [21]
Myocardial infarction DIS655KI Strong Genetic Variation [12]
Nasal polyp DISLP3XE Strong Biomarker [6]
Neoplasm DISZKGEW Strong Genetic Variation [22]
Osteoporosis DISF2JE0 Strong Biomarker [23]
Plasma cell myeloma DIS0DFZ0 Strong Altered Expression [24]
Sarcoidosis DISE5B8Z Strong Genetic Variation [25]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [26]
Systemic lupus erythematosus DISI1SZ7 Strong Altered Expression [20]
Type-1 diabetes DIS7HLUB Strong Biomarker [27]
Uveal Melanoma DISA7ZGL Strong Altered Expression [28]
Vitiligo DISR05SL Strong Biomarker [29]
Chronic hepatitis B virus infection DISHL4NT moderate Genetic Variation [30]
Inflammation DISJUQ5T moderate Biomarker [31]
Rhabdomyosarcoma DISNR7MS moderate Biomarker [32]
Advanced cancer DISAT1Z9 Limited Biomarker [33]
B-cell neoplasm DISVY326 Limited Genetic Variation [34]
Glioma DIS5RPEH Limited Altered Expression [35]
Lymphoma DISN6V4S Limited Altered Expression [36]
Melanoma DIS1RRCY Limited Altered Expression [37]
Nasopharyngeal carcinoma DISAOTQ0 Limited Altered Expression [38]
Nervous system inflammation DISB3X5A Limited Biomarker [5]
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⏷ Show the Full List of 43 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 MHC class II transactivator (CIITA). [39]
Arsenic DMTL2Y1 Approved Arsenic increases the methylation of MHC class II transactivator (CIITA). [41]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of MHC class II transactivator (CIITA). [49]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of MHC class II transactivator (CIITA). [40]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of MHC class II transactivator (CIITA). [42]
Zoledronate DMIXC7G Approved Zoledronate increases the expression of MHC class II transactivator (CIITA). [43]
Azacitidine DMTA5OE Approved Azacitidine increases the expression of MHC class II transactivator (CIITA). [44]
Melphalan DMOLNHF Approved Melphalan decreases the expression of MHC class II transactivator (CIITA). [45]
Alitretinoin DMME8LH Approved Alitretinoin increases the expression of MHC class II transactivator (CIITA). [40]
Diphenylpyraline DMW4X37 Approved Diphenylpyraline increases the expression of MHC class II transactivator (CIITA). [46]
Ritonavir DMU764S Approved Ritonavir increases the expression of MHC class II transactivator (CIITA). [47]
Nevirapine DM6HX9B Approved Nevirapine increases the expression of MHC class II transactivator (CIITA). [47]
Tamibarotene DM3G74J Phase 3 Tamibarotene increases the expression of MHC class II transactivator (CIITA). [40]
Verapamil DMA7PEW Phase 2/3 Trial Verapamil affects the expression of MHC class II transactivator (CIITA). [48]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of MHC class II transactivator (CIITA). [50]
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⏷ Show the Full List of 12 Drug(s)

References

1 New fusion transcripts identified in normal karyotype acute myeloid leukemia.PLoS One. 2012;7(12):e51203. doi: 10.1371/journal.pone.0051203. Epub 2012 Dec 12.
2 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.
3 MHC2TA and FCRL3 genes are not associated with rheumatoid arthritis in Mexican patients.Rheumatol Int. 2016 Feb;36(2):249-54. doi: 10.1007/s00296-015-3358-2. Epub 2015 Sep 8.
4 Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency.J Clin Endocrinol Metab. 2008 Sep;93(9):3310-7. doi: 10.1210/jc.2008-0821. Epub 2008 Jul 1.
5 Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases.Immunology. 2017 Apr;150(4):408-417. doi: 10.1111/imm.12692. Epub 2016 Dec 22.
6 Genetic association analysis of CIITA variations with nasal polyp pathogenesis in asthmatic patients.Mol Med Rep. 2013 Mar;7(3):927-34. doi: 10.3892/mmr.2012.1251. Epub 2012 Dec 27.
7 IL-1 beta inhibits IFN-gamma-induced class II MHC expression by suppressing transcription of the class II transactivator gene.J Immunol. 1999 Jan 15;162(2):886-96.
8 Recurrent genomic rearrangements in primary testicular lymphoma.J Pathol. 2015 Jun;236(2):136-41. doi: 10.1002/path.4522. Epub 2015 Mar 26.
9 Genetic Variations of NLR family genes in Behcet's Disease.Sci Rep. 2016 Feb 1;6:20098. doi: 10.1038/srep20098.
10 Downregulation of HLA class I gene transcription in choriocarcinoma cells is controlled by the proximal promoter element and can be reversed by CIITA.Placenta. 1999 May;20(4):293-301. doi: 10.1053/plac.1998.0380.
11 Role of inflammatory related gene expression in clear cell renal cell carcinoma development and clinical outcomes.J Urol. 2011 Nov;186(5):2071-7. doi: 10.1016/j.juro.2011.06.049. Epub 2011 Sep 23.
12 Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes.Genes Immun. 2012 Dec;13(8):632-40. doi: 10.1038/gene.2012.44. Epub 2012 Oct 11.
13 A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.
14 Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.PLoS One. 2015 Oct 14;10(10):e0139740. doi: 10.1371/journal.pone.0139740. eCollection 2015.
15 Translocation (16;18)(p13;q21.3) in follicular lymphoma.Cancer Genet Cytogenet. 2004 Oct 15;154(2):160-2. doi: 10.1016/j.cancergencyto.2004.02.008.
16 Single nucleotide polymorphisms and functional analysis of class II transactivator (CIITA) promoter IV in persistent HBV infection.J Clin Virol. 2007 Nov;40(3):197-201. doi: 10.1016/j.jcv.2007.08.016.
17 Evolutionary conservation and characterization of the bare lymphocyte syndrome transcription factor RFX-B and its paralogue ANKRA2.Immunogenetics. 2005 Feb;56(11):788-97. doi: 10.1007/s00251-004-0738-2. Epub 2005 Jan 18.
18 Role of the MHC2TA gene in autoimmune diseases.Ann Rheum Dis. 2007 Mar;66(3):325-9. doi: 10.1136/ard.2006.059428. Epub 2006 Sep 29.
19 The MHC2TA-168A/G and +1614G/C polymorphisms and risk for multiple sclerosis or chronic inflammatory arthropathies.Tissue Antigens. 2007 Sep;70(3):247-51. doi: 10.1111/j.1399-0039.2007.00876.x.
20 Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells.Ann Rheum Dis. 2019 Apr;78(4):519-528. doi: 10.1136/annrheumdis-2018-214323. Epub 2019 Jan 23.
21 Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma.Blood. 2019 Sep 5;134(10):802-813. doi: 10.1182/blood.2019001126. Epub 2019 Jul 10.
22 Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults.Histopathology. 2020 Mar;76(4):509-520. doi: 10.1111/his.14023. Epub 2020 Feb 21.
23 MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity.J Bone Miner Res. 2014 Feb;29(2):290-303. doi: 10.1002/jbmr.2090.
24 MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma.Mol Immunol. 2007 Apr;44(11):2923-32. doi: 10.1016/j.molimm.2007.01.009. Epub 2007 Feb 14.
25 Major histocompatibility complex class II transactivator gene polymorphism: associations with Lfgren's syndrome.Tissue Antigens. 2010 Aug;76(2):96-101. doi: 10.1111/j.1399-0039.2010.01476.x. Epub 2010 Mar 10.
26 Histone deacetylation, but not hypermethylation, modifies class II transactivator and MHC class II gene expression in squamous cell carcinomas.J Immunol. 2003 May 15;170(10):4980-5. doi: 10.4049/jimmunol.170.10.4980.
27 Variability in the CIITA gene interacts with HLA in multiple sclerosis.Genes Immun. 2014 Apr-May;15(3):162-7. doi: 10.1038/gene.2013.71. Epub 2014 Jan 16.
28 A role for EZH2 in silencing of IFN-gamma inducible MHC2TA transcription in uveal melanoma.J Immunol. 2007 Oct 15;179(8):5317-25. doi: 10.4049/jimmunol.179.8.5317.
29 Evaluation of NLRP1 gene polymorphisms in Vogt-Koyanagi-Harada disease.Jpn J Ophthalmol. 2011 Jan;55(1):57-61. doi: 10.1007/s10384-010-0887-9. Epub 2011 Feb 18.
30 Relationship between polymorphism of class II transactivator gene promoters and chronic hepatitis B.World J Gastroenterol. 2005 Feb 14;11(6):854-7. doi: 10.3748/wjg.v11.i6.854.
31 NOD-LRR proteins: role in host-microbial interactions and inflammatory disease.Annu Rev Biochem. 2005;74:355-83. doi: 10.1146/annurev.biochem.74.082803.133347.
32 CIITA is silenced by epigenetic mechanisms that prevent the recruitment of transactivating factors in rhabdomyosarcoma cells.Int J Cancer. 2012 Aug 15;131(4):E437-48. doi: 10.1002/ijc.26478. Epub 2012 Jan 11.
33 Restriction factors in human retrovirus infections and the unprecedented case of CIITA as link of intrinsic and adaptive immunity against HTLV-1.Retrovirology. 2019 Nov 29;16(1):34. doi: 10.1186/s12977-019-0498-6.
34 Prognostic and clinicopathological significance of PD-1/PD-L1 expression in the tumor microenvironment and neoplastic cells for lymphoma.Int Immunopharmacol. 2019 Dec;77:105999. doi: 10.1016/j.intimp.2019.105999. Epub 2019 Nov 6.
35 Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA).Glia. 2004 Mar;45(4):392-405. doi: 10.1002/glia.10343.
36 Defective class II transactivator expression in a B lymphoma cell line.Leukemia. 2004 Apr;18(4):832-40. doi: 10.1038/sj.leu.2403315.
37 Oncogene-Expressing Senescent Melanocytes Up-Regulate MHC Class II, aCandidate Melanoma Suppressor Function.J Invest Dermatol. 2017 Oct;137(10):2197-2207. doi: 10.1016/j.jid.2017.05.030. Epub 2017 Jun 22.
38 An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma.Hum Mol Genet. 2016 Aug 15;25(16):3626-3634. doi: 10.1093/hmg/ddw200. Epub 2016 Jul 19.
39 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.
40 Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
41 Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
42 Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
43 Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
44 The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
45 Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
46 Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
47 Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
48 Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
49 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.
50 Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.