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Gene Review

CIITA  -  class II, major histocompatibility complex...

Homo sapiens

Synonyms: C2TA, CIITAIV, MHC class II transactivator, MHC2TA, NLRA
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Disease relevance of CIITA


High impact information on CIITA

  • The study of RFX and CIITA has made major contributions to our comprehension of the molecular mechanisms controlling MHCII genes and has made this system into a textbook model for the regulation of gene expression [7].
  • A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators [8].
  • Naip5 is involved in host resistance to Legionella pneumophila through cell autonomous mechanisms, whereas CIITA plays a critical role in antigen presentation and development of antigen-specific T lymphocytes [9].
  • We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components [10].
  • METHODS: To elucidate the genetic defect in patients with MHC class II deficiency that was not classified genetically, we performed direct complementation assays with the three genes known to regulate the expression of MHC class II genes, CIITA, RFX5, and RFXAP, and the relevant mutations were identified in each patient [11].

Chemical compound and disease context of CIITA

  • We suggest that the high endogenous cortisol level observed in septic shock may be a possible new factor involved in the loss of HLA-DR expression on monocytes via its effect on HLA-DR and CIITA transcription [12].
  • Expression of the gene encoding the transactivator CIITA in C6 gliomas using an EBV-based transduction system led to induction of MHC I and II and thereby mimicked therapeutic responses that could not operate in syngeneic models [13].

Biological context of CIITA


Anatomical context of CIITA

  • In contrast to these events, fetal trophoblast-like cell lines, which are refractory to CIITA induction by IFN-gamma, failed to assemble the above factors or modify their chromatin, suggesting that accessibility to the promoter is blocked [17].
  • Together, these results argue for an important role of DNA hyper-methylation in the control of CIITA expression in leukemic T cells [18].
  • The class II trans-activator (CIITA), which acts as a master regulator for expression of MHC class II genes, is expressed constitutively in mature B cells [19].
  • The lack of invariant chain expression correlated with lack of CIITA-mediated transactivation of the invariant chain promoter in transient transfection assays in SSI fibroblast cells [20].
  • This is the first evidence that phagocytosis of bacteria can down-modulate HLA class II expression in normal human macrophages by acting at the level of expression of CIITA [21].

Associations of CIITA with chemical compounds


Physical interactions of CIITA


Enzymatic interactions of CIITA

  • The decrease in CIITA expression by PKCdelta inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter [29].

Regulatory relationships of CIITA


Other interactions of CIITA

  • It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process [16].
  • The culture supernatant containing IFN-alpha/beta, on the other hand, inhibited MHC class II expression without affecting STAT1 and CIITA expression [33].
  • It cooperates with IRF-1 in the activation of the CIITA type IV promoter and can co-occupy the IRF-E of the promoter with IRF-1 [34].
  • The most upstream module consists of the enhancer A and ISRE, and mediates constitutive and cytokine induced expression, whereas the SXY module is important for the constitutive and CIITA-mediated transactivation of MHC class I genes [35].
  • HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA [35].

Analytical, diagnostic and therapeutic context of CIITA


  1. Identification of the ankyrin repeat proteins ANKRA and RFXANK as novel partners of class IIa histone deacetylases. Wang, A.H., Grégoire, S., Zika, E., Xiao, L., Li, C.S., Li, H., Wright, K.L., Ting, J.P., Yang, X.J. J. Biol. Chem. (2005) [Pubmed]
  2. Downregulation of HLA class I gene transcription in choriocarcinoma cells is controlled by the proximal promoter element and can be reversed by CIITA. Lefebvre, S., Moreau, P., Dausset, J., Carosella, E.D., Paul, P. Placenta (1999) [Pubmed]
  3. Constitutive and IFNgamma-induced activation of MHC2TA promoter type III in human melanoma cell lines is governed by separate regulatory elements within the PIII upstream regulatory region. van der Stoep, N., Quinten, E., Alblas, G., Plancke, A., van Eggermond, M.C., Holling, T.M., van den Elsen, P.J. Mol. Immunol. (2007) [Pubmed]
  4. MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Zhao, M., Flynt, F.L., Hong, M., Chen, H., Gilbert, C.A., Briley, N.T., Bolick, S.C., Wright, K.L., Piskurich, J.F. Mol. Immunol. (2007) [Pubmed]
  5. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Kanazawa, S., Okamoto, T., Peterlin, B.M. Immunity (2000) [Pubmed]
  6. Role of the MHC2TA gene in autoimmune diseases. Martínez, A., Sánchez-Lopez, M., Varadé, J., Mas, A., Martín, M.C., de Las Heras, V., Arroyo, R., Mendoza, J.L., Díaz-Rubio, M., Fernández-Gutiérrez, B., de la Concha, E.G., Urcelay, E. Ann. Rheum. Dis. (2007) [Pubmed]
  7. The bare lymphocyte syndrome and the regulation of MHC expression. Reith, W., Mach, B. Annu. Rev. Immunol. (2001) [Pubmed]
  8. Regulation of MHC class II genes: lessons from a disease. Mach, B., Steimle, V., Martinez-Soria, E., Reith, W. Annu. Rev. Immunol. (1996) [Pubmed]
  9. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Inohara, n.u.l.l., Chamaillard, n.u.l.l., McDonald, C., Nuñez, G. Annu. Rev. Biochem. (2005) [Pubmed]
  10. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Swanberg, M., Lidman, O., Padyukov, L., Eriksson, P., Akesson, E., Jagodic, M., Lobell, A., Khademi, M., Börjesson, O., Lindgren, C.M., Lundman, P., Brookes, A.J., Kere, J., Luthman, H., Alfredsson, L., Hillert, J., Klareskog, L., Hamsten, A., Piehl, F., Olsson, T. Nat. Genet. (2005) [Pubmed]
  11. Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency. Villard, J., Lisowska-Grospierre, B., van den Elsen, P., Fischer, A., Reith, W., Mach, B. N. Engl. J. Med. (1997) [Pubmed]
  12. Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Le Tulzo, Y., Pangault, C., Amiot, L., Guilloux, V., Tribut, O., Arvieux, C., Camus, C., Fauchet, R., Thomas, R., Drénou, B. Am. J. Respir. Crit. Care Med. (2004) [Pubmed]
  13. Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model. Beutler, A.S., Banck, M.S., Wedekind, D., Hedrich, H.J. Hum. Gene Ther. (1999) [Pubmed]
  14. Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. Pattenden, S.G., Klose, R., Karaskov, E., Bremner, R. EMBO J. (2002) [Pubmed]
  15. Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. Masternak, K., Reith, W. EMBO J. (2002) [Pubmed]
  16. Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression. Zika, E., Fauquier, L., Vandel, L., Ting, J.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. Kinetics of a gamma interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Morris, A.C., Beresford, G.W., Mooney, M.R., Boss, J.M. Mol. Cell. Biol. (2002) [Pubmed]
  18. Regulation of MHC class II expression in human T-cell malignancies. Holling, T.M., Schooten, E., Langerak, A.W., van den Elsen, P.J. Blood (2004) [Pubmed]
  19. Transcriptional regulation of the MHC class II trans-activator (CIITA) promoter III: identification of a novel regulatory region in the 5'-untranslated region and an important role for cAMP-responsive element binding protein 1 and activating transcription factor-1 in CIITA-promoter III transcriptional activation in B lymphocytes. van der Stoep, N., Quinten, E., van den Elsen, P.J. J. Immunol. (2002) [Pubmed]
  20. Discoordinate expression of invariant chain and MHC class II genes in class II transactivator-transfected fibroblasts defective for RFX5. Peijnenburg, A., Van Eggermond, M.J., Gobin, S.J., Van den Berg, R., Godthelp, B.C., Vossen, J.M., Van den Elsen, P.J. J. Immunol. (1999) [Pubmed]
  21. Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation. Barbaro, A.d.e. .L., Tosi, G., Frumento, G., Bruschi, E., D'Agostino, A., Valle, M.T., Manca, F., Accolla, R.S. Eur. J. Immunol. (2002) [Pubmed]
  22. CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocompatibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation. Hake, S.B., Masternak, K., Kammerbauer, C., Janzen, C., Reith, W., Steimle, V. Mol. Cell. Biol. (2000) [Pubmed]
  23. Associations and interactions between bare lymphocyte syndrome factors. DeSandro, A.M., Nagarajan, U.M., Boss, J.M. Mol. Cell. Biol. (2000) [Pubmed]
  24. Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Spilianakis, C., Papamatheakis, J., Kretsovali, A. Mol. Cell. Biol. (2000) [Pubmed]
  25. Increased binding of IFN regulating factor 1 mediates the synergistic induction of CIITA by IFN-gamma and tumor necrosis factor-alpha in human thyroid carcinoma cells. Rahat, M.A., Chernichovski, I., Lahat, N. Int. Immunol. (2001) [Pubmed]
  26. The S box of major histocompatibility complex class II promoters is a key determinant for recruitment of the transcriptional co-activator CIITA. Muhlethaler-Mottet, A., Krawczyk, M., Masternak, K., Spilianakis, C., Kretsovali, A., Papamatheakis, J., Reith, W. J. Biol. Chem. (2004) [Pubmed]
  27. The class II trans-activator CIITA interacts with the TBP-associated factor TAFII32. Fontes, J.D., Jiang, B., Peterlin, B.M. Nucleic Acids Res. (1997) [Pubmed]
  28. Multiple interactions between BRG1 and MHC class II promoter binding proteins. Mudhasani, R., Fontes, J.D. Mol. Immunol. (2005) [Pubmed]
  29. Role of PKCdelta in IFN-gamma-inducible CIITA gene expression. Kwon, M.J., Yao, Y., Walter, M.J., Holtzman, M.J., Chang, C.H. Mol. Immunol. (2007) [Pubmed]
  30. Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation. Zika, E., Greer, S.F., Zhu, X.S., Ting, J.P. Mol. Cell. Biol. (2003) [Pubmed]
  31. Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Pachot, A., Monneret, G., Brion, A., Venet, F., Bohé, J., Bienvenu, J., Mougin, B., Lepape, A. Crit. Care Med. (2005) [Pubmed]
  32. Interferon type I downregulates human parainfluenza virus type 3-induced major histocompatibility complex class II expression. Gao, J., De, B.P., Banerjee, A.K. Viral Immunol. (2002) [Pubmed]
  33. Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon. Gao, J., De, B.P., Han, Y., Choudhary, S., Ransohoff, R., Banerjee, A.K. J. Virol. (2001) [Pubmed]
  34. Interferon regulatory factor-2 point mutations in human pancreatic tumors. Xi, H., Blanck, G. Int. J. Cancer (2000) [Pubmed]
  35. Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G. Gobin, S.J., van den Elsen, P.J. Hum. Immunol. (2000) [Pubmed]
  36. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. Miller, D.M., Rahill, B.M., Boss, J.M., Lairmore, M.D., Durbin, J.E., Waldman, J.W., Sedmak, D.D. J. Exp. Med. (1998) [Pubmed]
  37. Regulation and specificity of MHC2TA promoter usage in human primary T lymphocytes and cell line. Wong, A.W., Ghosh, N., McKinnon, K.P., Reed, W., Piskurich, J.F., Wright, K.L., Ting, J.P. J. Immunol. (2002) [Pubmed]
  38. Major histocompatibility class II transactivator (CIITA) mediates repression of collagen (COL1A2) transcription by interferon gamma (IFN-gamma). Xu, Y., Wang, L., Butticè, G., Sengupta, P.K., Smith, B.D. J. Biol. Chem. (2004) [Pubmed]
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