Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.

Abstract

SummaryIn 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 fl2-microglobulin (fl2m) at rates comparable to those found for HLA-A and -B, and increased competition for fl2m 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, '~600 bases downstream of the translation stop codon.

A Single Bottleneck in HLA-C Assembly

“…In contrast, McCutcheon et al (10) did not find evidence for impaired assembly of HLA-Cw3, -Cw6, and -Cw7 complexes and found that assembled HLA-A2, -B27, and -Cw1 complexes are equally long-lived. Taking advantage of the distribution of the L31 epitope on a set of alleles that includes one member from each of the eight serologically defined HLA-C specificities and five HLA-B alleles, we have been able to carry out a homogeneous comparison of the accumulation of the different unfolded heavy chains and to estimate their assembly abilities.…”

“…Also in contrast to HLA-A and HLA-B, HLA-C is a rather poor assembler. This latter feature has been proposed to correlate with impaired intracellular transport and low surface expression (8,9), although this conclusion has been questioned (10).…”

Isolated HLA-C mismatches in unrelated donor transplantation for CML

“…In all, 24 patients (21%), however, were mismatched for HLA-C only (Table 1), which allowed the analysis of the significance of this locus which is expressed at lower levels than other class I antigens. 21 The 79 HLA allele-mismatches were distributed as follows: five HLA-A (two single mismatches), 13 HLA-B (6), 36 HLA-C (24), seven DRB1 (4), seven DRB3 (4) and 11 DQB1 (2). No DRB5 incompatibility was detected.…”

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

“…HLA-C molecules are expressed at a low level on the cell surface compared with HLA-A and -B (1)(2)(3)(4)(5), owing in part to the poor assembly of HLA-C heavy chains with β2 microglobulin (2,4) and the retention of HLA-C molecules in the endoplasmic reticulum, where they are partially degraded (3). An internalization and lysosomal targeting signal in the cytoplasmic tail of HLA-C further regulates its surface expression (6).…”