Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.
Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.
复制标题
DOI：
10.1084/jem.181.6.2085
复制
发表时间：
1995-06-01
期刊：
影响因子：
--
通讯作者：
Parham P
中科院分区：
文献类型：
--
作者：
McCutcheon JA;Gumperz J;Smith KD;Lutz CT;Parham P
与人类白细胞抗原-A和-B相比，人类白细胞抗原-C基因座的蛋白产物的特性较差，部分原因是它们在细胞表面的表达水平较低。在这里，我们研究了在组装和mRNA水平的调节过程中蛋白质-蛋白质的相互作用如何影响细胞表面的HLA-C的表达。我们发现，人类白细胞抗原-C重链蛋白的固有特性与细胞表面低表达无关：人类白细胞抗原-C重链与β2-微球蛋白(β2m)结合和解离的速度与发现的人类白细胞抗原-A和-B相当，对β2m的竞争增加并不改变其表面表达。通过对HLA-B7和-Cw3基因拼接的嵌合基因的研究，我们发现含有B7肽结合槽的嵌合蛋白可以具有较低的细胞表面表达，这表明结合多肽的效率低下并不是导致HLA-C细胞表面表达较低的原因。转染细胞表面的人类白细胞抗原-A、-B或-C的表达水平相似，提示人类白细胞抗原-C重链基因的非编码区参与了表面表达的调控。我们发现，与人类白细胞抗原-B相比，人类白细胞抗原-C基因的表达水平较低，并且这种差异是由于人类白细胞抗原-C信息的快速降解所致。对嵌合的B7/Cw3和B7/CW6基因的实验表明，在外显子3的3‘端和翻译终止密码子下游约600个碱基的3’非翻译区之间可以找到一个决定人类白细胞抗原-C低表达的区域。
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.