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Gene Review

RFX5  -  regulatory factor X, 5 (influences HLA...

Homo sapiens

Synonyms: DNA-binding protein RFX5, Regulatory factor X 5
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Disease relevance of RFX5

  • DNA-binding defects in the protein RFX5 cause bare lymphocyte syndrome or major histocompatibility antigen class II deficiency [1].
  • We have characterised the mutations in all four patients known to harbour a defect in the RFX5 gene and have mapped this new human disease gene to chromosome 1 band q21, a region frequently exhibiting chromosomal aberrations in a variety of preneoplastic and neoplastic diseases [2].
  • CPAF mutants deficient in processing even when expressed by E. coli failed to degrade RFX5 [3].
  • Hybrid protein effectors between RFX1 and RFX5 and the activation domain of VP16 from the herpes simplex virus were co-expressed with plasmid targets, which contained the isolated X box, X box and selected flanking CUS, or the entire DRA promoter [4].

High impact information on RFX5

  • A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators [5].
  • The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients [5].
  • Transfection of the patient's cells with the RFX5 cDNA repairs the binding defect and fully restores expression of all the endogenous MHC class II genes in vivo [6].
  • Nevertheless, RFX5-/- mice develop a severe immunodeficiency due to the lack of MHC-II in thymic cortex, failure of positive selection of CD4+ T cells, and absence of MHC-II on resting B cells and resident or IFNgamma-activated macrophages [7].
  • While the pivotal role of CIITA for MHC-II gene transcription is supported by the essential absence of MHC-II molecules in CIITA-deficient mice, we demonstrate here that RFX5-/- mice retain expression of MHC-II in thymic medulla, mature dendritic cells, and activated B cells [7].

Biological context of RFX5


Anatomical context of RFX5

  • Also, RFX5 represses transcription of a collagen promoter-reporter construct in rat fibroblasts that have no detectable RFX5 complex formation or protein [10].
  • Genetic complementation of a B-lymphocyte cell line from such a patient with a cDNA expression library has allowed us to isolate RFX5, the regulatory gene responsible for the MHC class II deficiency [6].
  • Here, we show that the defect in G1B, one such cell line, is attributed to the lack of functional RFX5, the largest subunit of RFX [12].
  • In addition to lack of CIITA expression, trophoblast cells also displayed a repressed expression of RFX5 [13].
  • This differential requirement for CIITA and RFX5 in subsets of antigen-presenting cells may be specific for the mouse; it may, however, also exist in humans without having been noticed so far [7].

Associations of RFX5 with chemical compounds

  • RFX5 was found to interact with CIITA, and this interaction was dependent on a proline-rich domain within RFX5 [14].
  • This mutation lies outside of previously defined functional domains of RFX5 but within an unusual, leucine-rich region (62-LYLYLQL-68) [12].
  • Moreover, simvastatin lowers the IFN-gamma-induced expression of RFX5 and MHC II in addition to repressing collagen expression [15].
  • We further demonstrate that a lactacystin-sensitive proteasome-like activity identified in chlamydia-infected cell cytosolic fraction can degrade both USF-1 and RFX5 [16].

Physical interactions of RFX5

  • In normal cells, RFX5 complex along with major histocompatibility class II transactivator (CIITA) is induced by interferon-gamma to occupy this site and repress collagen transcription (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319-41332) [17].

Regulatory relationships of RFX5


Other interactions of RFX5


Analytical, diagnostic and therapeutic context of RFX5


  1. Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding. Gajiwala, K.S., Chen, H., Cornille, F., Roques, B.P., Reith, W., Mach, B., Burley, S.K. Nature (2000) [Pubmed]
  2. Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. Villard, J., Reith, W., Barras, E., Gos, A., Morris, M.A., Antonarakis, S.E., Van den Elsen, P.J., Mach, B. Hum. Mutat. (1997) [Pubmed]
  3. Cleavage-dependent activation of a chlamydia-secreted protease. Dong, F., Pirbhai, M., Zhong, Y., Zhong, G. Mol. Microbiol. (2004) [Pubmed]
  4. Assembly of functional regulatory complexes on MHC class II promoters in vivo. Fontes, J.D., Jabrane-Ferrat, N., Peterlin, B.M. J. Mol. Biol. (1997) [Pubmed]
  5. Regulation of MHC class II genes: lessons from a disease. Mach, B., Steimle, V., Martinez-Soria, E., Reith, W. Annu. Rev. Immunol. (1996) [Pubmed]
  6. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Steimle, V., Durand, B., Barras, E., Zufferey, M., Hadam, M.R., Mach, B., Reith, W. Genes Dev. (1995) [Pubmed]
  7. Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice. Clausen, B.E., Waldburger, J.M., Schwenk, F., Barras, E., Mach, B., Rajewsky, K., Förster, I., Reith, W. Immunity (1998) [Pubmed]
  8. A functionally essential domain of RFX5 mediates activation of major histocompatibility complex class II promoters by promoting cooperative binding between RFX and NF-Y. Villard, J., Peretti, M., Masternak, K., Barras, E., Caretti, G., Mantovani, R., Reith, W. Mol. Cell. Biol. (2000) [Pubmed]
  9. Interferon gamma repression of collagen (COL1A2) transcription is mediated by the RFX5 complex. Xu, Y., Wang, L., Buttice, G., Sengupta, P.K., Smith, B.D. J. Biol. Chem. (2003) [Pubmed]
  10. The RFX family interacts at the collagen (COL1A2) start site and represses transcription. Sengupta, P.K., Fargo, J., Smith, B.D. J. Biol. Chem. (2002) [Pubmed]
  11. A hierarchy of nuclear localization signals governs the import of the regulatory factor X complex subunits and MHC class II expression. Nagarajan, U.M., Long, A.B., Harreman, M.T., Corbett, A.H., Boss, J.M. J. Immunol. (2004) [Pubmed]
  12. Analysis of the defect in IFN-gamma induction of MHC class II genes in G1B cells: identification of a novel and functionally critical leucine-rich motif (62-LYLYLQL-68) in the regulatory factor X 5 transcription factor. Brickey, W.J., Wright, K.L., Zhu, X.S., Ting, J.P. J. Immunol. (1999) [Pubmed]
  13. Transcriptional control of MHC genes in fetal trophoblast cells. van den Elsen, P.J., Gobin, S.J., van der Stoep, N., Datema, G., Viëtor, H.E. J. Reprod. Immunol. (2001) [Pubmed]
  14. Associations and interactions between bare lymphocyte syndrome factors. DeSandro, A.M., Nagarajan, U.M., Boss, J.M. Mol. Cell. Biol. (2000) [Pubmed]
  15. Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells. Butticè, G., Miller, J., Wang, L., Smith, B.D. Circ. Res. (2006) [Pubmed]
  16. Degradation of transcription factor RFX5 during the inhibition of both constitutive and interferon gamma-inducible major histocompatibility complex class I expression in chlamydia-infected cells. Zhong, G., Liu, L., Fan, T., Fan, P., Ji, H. J. Exp. Med. (2000) [Pubmed]
  17. Collagen alpha1(I) gene (COL1A1) is repressed by RFX family. Sengupta, P., Xu, Y., Wang, L., Widom, R., Smith, B.D. J. Biol. Chem. (2005) [Pubmed]
  18. Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Scholl, T., Mahanta, S.K., Strominger, J.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Masternak, K., Barras, E., Zufferey, M., Conrad, B., Corthals, G., Aebersold, R., Sanchez, J.C., Hochstrasser, D.F., Mach, B., Reith, W. Nat. Genet. (1998) [Pubmed]
  20. 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]
  21. Regulatory factor for X-box family proteins differentially interact with histone deacetylases to repress collagen alpha2(I) gene (COL1A2) expression. Xu, Y., Sengupta, P.K., Seto, E., Smith, B.D. J. Biol. Chem. (2006) [Pubmed]
  22. Expression and translocation of chlamydial protease during acute and persistent infection of the epithelial HEp-2 cells with Chlamydophila (Chlamydia) pneumoniae. Heuer, D., Brinkmann, V., Meyer, T.F., Szczepek, A.J. Cell. Microbiol. (2003) [Pubmed]
  23. Assembly of major histocompatability complex (MHC) class II transcription factors: association and promoter recognition of RFX proteins. Burd, A.L., Ingraham, R.H., Goldrick, S.E., Kroe, R.R., Crute, J.J., Grygon, C.A. Biochemistry (2004) [Pubmed]
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