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Abstract
Recent analyses of the upstream regulatory regions of the class I major histocompatibility complex genes in higher primates provided a generalized structural basis for the differential expression of A- and B-locus gene products in response to specific physiological stimulus. Among the regulatory sequences that differ between the loci is the interferon-responsive element (IRE). While the B-IRE is conserved, the A-IREs have species-specific sequence variation. We previously demonstrated that the B-IRE was an interferon (IFN)-inducible enhancer, whereas none of the A-IREs were functional. In the present study, we examined the biochemical basis for the enhancer activity of the conserved B-IRE and found that this may be attributed to a novel gamma-IFN-inducible factor. This factor accumulated in nuclei of cells within minutes of exposure to gamma-IFN. Its appearance was independent of de novo protein synthesis. However, it was not detected in nuclei of cells treated with herbimycin A, suggesting that its appearance depends on a protein kinase activation pathway. Supershift assays indicated that it was distinct from STAT1alpha, IFN regulatory factor-1, and p48, transcription factors known to bind IRE-like sequences found in regulatory regions of many non-major histocompatibility complex gamma-IFN-responsive genes. Competition assays show that this novel factor bound B-IRE with relatively high affinity, about 100-fold more than that for the A-IRE sequence. This factor was also present in STAT1alpha and p48 somatic mutants that also exhibited B-IRE enhancer activity in reporter gene bioassays in a manner similar to those seen with wild type cells. These observations indicate the existence of a novel gamma-IFN-dependent transcriptional activation pathway that correlates with the differential enhancer activity of the HLA-B IRE.
Highlights
In humans, the expression of class I HLA-A and -B glycoproteins is not tightly coordinated [5]
It is important to note that the conserved B-interferon-responsive element (IRE) motif in the higher primates is the identical sequence found among the classical class I major histocompatibility complex (MHC) genes of phylogenetically lower mammals and that these orthologous genes are responsive to ␥-IFN [40, 42, 43]
By virtue of the design of reporter gene constructs in which the 12-nucleotide core B-IRE sequence flanked by MHC A-locus sequences, the enhancer activity of the element was attributed to a single nucleotide in the middle of the sequence, i.e. an A 3 T change between the B-IRE and the A-IREs
Summary
The expression of class I HLA-A and -B glycoproteins is not tightly coordinated [5]. These accumulating changes in the A-promoters during phylogeny are correlated with fewer transcription factor binding motifs These observations provide a phylogenetic basis for the differential regulation of expression of class I MHC genes. It is important to note that the conserved B-IRE motif in the higher primates is the identical sequence found among the classical class I MHC genes of phylogenetically lower mammals and that these orthologous genes are responsive to ␥-IFN [40, 42, 43]. This suggests a common ␥-IFN-inducible regulatory machinery for the mammalian class I MHC genes. Evidence is presented for a novel ␥-IFN-inducible factor that correlates with the strong enhancer activity of the MHC class I B-locus IRE
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