Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States.
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
Front Immunol. 2020 Jan 10;10:3034. doi: 10.3389/fimmu.2019.03034. eCollection 2019.
A complex system regulating HLA-C expression in NK cells, driven by an NK-specific promoter that produces alternatively spliced variants of the 5'-UTR has been recently identified. Exon content of the NK-specific 5'-UTR varies strikingly across alleles, with some exons being allele specific. In order to investigate the possibility that allelic variation in the 5'-UTR modulates HLA-C expression levels, cDNAs containing several distinct classes of 5'-UTR were compared. Subtle changes in 5'-UTR content had a significant effect on the expression of and cDNA clones, suggesting that alternative splicing can fine-tune the level of protein expression. The allele was found to be highly expressed in relation to the other alleles studied. However, its increased expression was primarily associated with differences in the peptide-binding groove. Although the impact of allele-specific alternative splicing of NK-Pro transcripts on protein levels can be modest when compared with the effect of changes in peptide-loading, alternative splicing may represent an additional regulatory mechanism to fine-tune HLA-C levels within NK cells in distinct tissue environments or at different stages of maturation in order to achieve optimal levels of missing-self recognition.
最近发现了一个复杂的系统，该系统调节 NK 细胞中 HLA-C 的表达，由一个 NK 特异性启动子驱动，该启动子产生 5'-UTR 的可变剪接变体。NK 特异性 5'-UTR 的外显子含量在不同的等位基因中差异显著，有些外显子是等位基因特异性的。为了研究 5'-UTR 中的等位基因变异是否调节 HLA-C 表达水平，比较了含有几种不同类型 5'-UTR 的 cDNA。5'-UTR 含量的细微变化对 和 cDNA 克隆的表达有显著影响，表明可变剪接可以精细调节蛋白表达水平。与研究的其他等位基因相比， 等位基因的表达水平较高。然而，其表达增加主要与肽结合槽的差异有关。尽管与肽加载的变化相比，NK-Pro 转录物的等位基因特异性可变剪接对蛋白水平的影响可能较小，但可变剪接可能代表一种额外的调节机制，以在不同的组织环境或在不同的成熟阶段微调 NK 细胞中的 HLA-C 水平，以实现缺失自我识别的最佳水平。
