A common mutation in the hominoid class I A-locus IFN-responsive element results in the loss of enhancer activity.
Despite the observed coordinate expression of HLA-A and -B antigens in somatic tissues, there is growing evidence that the A and B class I genes are differentially regulated at the transcriptional level. Previous studies indicate that this may be related to locus-specific structural differences in certain enhancer elements. We have recently examined the 5' proximal regulatory regions of the A and B homologs in the higher non-human primates and found pronounced differences between the loci. Sequence analysis shows the B-promoters are more homogeneous, whereas the A-locus promoters are divergent among the various species examined. The differences in A- and B-promoters is exemplified by the regulatory element referred to as the IFN-responsive element (IRE). While the B-locus IRE is conserved among all primates examined, the A-locus IRE are divergent and reveal different sequences in the human/chimpanzee, gorilla and orang-utan. In reporter gene bioassays, the B-locus IRE exhibited an enhancer activity in response to induction with IFN-beta and IFN-gamma. In contrast, all the variants of the A-locus IRE found in hominoid primates were unresponsive to IFN. One base substitution shared by all the primate IREs proved to be inactivating. These results provide a molecular basis of how duplicated gene loci encoding structurally and functionally similar antigen-presenting molecules may become differentially responsive to physiological stimulus.
Vallejo
A N
AN
Department of Immunology, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Allen
K S
KS
Pease
L R
LR
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology*; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000235:genetics; D000882:Haplorhini; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1; D004915:Leukemia, Erythroblastic, Acute; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D010957:Plasmids; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D015234:HLA-A Antigens; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D008156:Luciferases