THE HUMAN-LEUKOCYTE ANTIGEN A2 INTERFERON-STIMULATED RESPONSE ELEMENTCONSENSUS SEQUENCE BINDS A NUCLEAR FACTOR REQUIRED FOR CONSTITUTIVE EXPRESSION

Both constitutive and interferon-inducible enhancer-like elements have been identified previously in the promoter of human leukocyte antigen (HLA) class I genes. One of these sites is termed the interferon-stim ulated response element (ISRE). We have tested the function of an ISRE consensus sequence in the human HLA class I gene HLA-A2 and confirmed previous studies that showed that the HLA-A2 ISRE consensus sequence does not mediate a response to interferons. However, deletion of the I SRE consensus sequence caused a severalfold reduction in the constitut ive expression of the HLA-A2 gene in K562 and Jurkat cells. Mobility s hift assays performed with the HLA-A2 ISRE revealed the presence of a constitutive binding protein (ISRE/CBP). This protein binds specifical ly to the HLA-A2 ISRE sequence, and binding is not efficiently compete d by the ISRE sequences of the HLA-B7 or ISG54 genes. Substitution of the HLA-B7 or ISG54 ISRE sequences for the HLA-A2 ISRE sequence caused a severalfold reduction in the constitutive expression of the HLA-A2 gene. Mass determinations showed the ISRE/CBP to be 105 kDa, different than any previously characterized ISRE binding proteins. We propose t hat ISRE/CBP is a novel positive transcriptional regulatory factor for the HLA-A2 gene that may contribute to the differential expression of HLA-A versus HLA-B genes.