Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.
In comparison with HLA-A and -B, the protein products of the HLA-C locus are poorly characterized, in part because of their low level of expression at the cell surface. Here, we examine how protein-protein interactions during assembly and regulation of the mRNA level affect cell surface expression of HLA-C. We find that intrinsic properties of the HLA-C heavy chain proteins do not correlate with low cell surface expression: HLA-C heavy chains associate and dissociate with beta 2-microglobulin (beta 2m) at rates comparable to those found for HLA-A and -B, and increased competition for beta 2m does not alter the surface expression of HLA-C. From studies of chimeric genes spliced from the HLA-B7 and -Cw3 genes, we find that chimeric proteins containing the B7 peptide-binding groove can have low cell surface expression, suggesting that inefficiency in binding peptides is not the cause of low cell surface expression for HLA-C. The surface levels of HLA-A, -B, or -C in cells transfected with cDNA can be similar, implicating noncoding regions of HLA-C heavy chain genes in the regulation of surface expression. We find that HLA-C mRNA is expressed at lower levels than HLA-B mRNA and that this difference results from faster degradation of the HLA-C message. Experiments examining chimeric B7/Cw3 and B7/Cw6 genes suggest that a region determining low expression of HLA-C is to be found between the 3' end of exon 3 and a site in the 3' untranslated region, approximately 600 bases downstream of the translation stop codon.
McCutcheon
J A
JA
Department of Structural Biology, Stanford University School of Medicine, California 94305, USA.
Gumperz
J
J
Smith
K D
KD
Lutz
C T
CT
Parham
P
P
D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D017931:DNA Primers; D015870:Gene Expression; D015234:HLA-A Antigens / Q000096:biosynthesis; D015235:HLA-B Antigens / Q000096:biosynthesis; D015236:HLA-C Antigens / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D001613:beta 2-Microglobulin / Q000378:metabolism
D017931:DNA Primers; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D046911:Macromolecular Substances; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin