Transactivation of classical and nonclassical HLA class I genes through the IFN-stimulated response element.
The IFN-stimulated response element (ISRE) is an important conserved cis-acting regulatory element in the promoter of MHC class I genes, but displays considerable locus-specific nucleotide variation. In this report, the putative ISREs of classical and nonclassical HLA class I genes were investigated for their contribution to MHC class I transactivation. It is shown that IFN-gamma induced MHC class I transactivation through the ISRE of HLA-A, HLA-B, HLA-C, and HLA-F. This is congruent with the binding of IFN regulatory factor-1 to the ISREs of these loci upon IFN-gamma treatment. Sp1 was shown to bind to the CG-rich sequences in the ISRE regions of HLA-B, HLA-C, and HLA-G. The putative E box 5' of the ISRE in most HLA-B alleles was shown to bind the upstream stimulatory factors (USF) 1 and 2. The Sp1 and USF binding sites did not influence IFN-gamma-induced transactivation. However, the USF binding site played a suppressive role in the constitutive expression of HLA-B. The locus-specific transcriptional control through the ISRE could be an important mechanism in the differential regulation of classical and nonclassical MHC class I expression, which determines adequate Ag presentation upon pathogenic challenge.
Department of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands. gobin@rullf2.Medfac.LeidenUniv.nl
S J
SJ
Gobin
M
M
van Zutphen
A M
AM
Woltman
P J
PJ
van den Elsen
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005805:Genes, MHC Class I / Q000276:immunology*; D005819:Genetic Markers; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020218:Response Elements / Q000276:immunology*; D016329:Sp1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology*; D014407:Tumor Cells, Cultured; D051720:Upstream Stimulatory Factors
D004268:DNA-Binding Proteins; D005819:Genetic Markers; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; D007371:Interferon-gamma