Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155
Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155
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DOI：
10.1128/jvi.01804-07
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发表时间：
2007-12-01
影响因子：
5.4
通讯作者：
Renne, Rolf
中科院分区：
文献类型：
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作者：
Skalsky, Rebecca L.;Samols, Mark A.;Renne, Rolf
microRNA（miRNAs）是一类非编码小RNA，通过与靶mRNA的3 '非翻译区（3' UTR）结合，在转录后调节基因表达。卡波西肉瘤相关疱疹病毒（KSHV）是一种与包括原发性渗出性淋巴瘤（PEL）在内的恶性肿瘤相关的病毒，编码12个miRNA基因，但只有少数调控靶点是已知的。我们发现KSRV-miR-K12-11与hsa-miR-155具有100%的种子序列同源性，hsa-miR-155是一种经常在淋巴瘤中上调的miRNA，对B细胞发育至关重要。基于这种种子序列的同源性，我们假设两种miRNAs调节一组共同的靶基因，因此可能具有相似的生物学活性。对五个PEL系的检查显示，PEL不表达miR-155，但表达高水平的miR-K12-11。生物信息学工具预测转录抑制因子BACH-1被两种miRNA靶向，并且miR-155或miR-K12-11的异位表达抑制含BACH-1 3 'UTR的报告基因。此外，在表达任一种miRNA的细胞中，BACH-1蛋白水平较低。表达miRNA的稳定细胞系的基因表达谱显示了66个通常下调的基因。对于选择的基因，通过报告基因测定证实miRNA靶向。因此，基于我们的计算机预测、报告基因测定和表达谱数据，miR-K12-11和miR-155调节一组共同的细胞靶点。鉴于miR-155在B细胞成熟过程中的作用，我们推测miR-K12-11可能有助于PEL细胞的独特发育表型，其在B细胞发育的晚期阶段被阻断。总之，这些发现表明KSHV miR-K12-11是miR-155的直系同源物。
MicroRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally regulate gene expression by binding to 3'-untranslated regions (3'UTRs) of target mRNAs. Kaposi's sarcoma-associated herpesvirus (KSHV), a virus linked to malignancies including primary effusion lymphoma (PEL), encodes 12 miRNA genes, but only a few regulatory targets are known. We found that KSRV-miR-K12-11 shares 100% seed sequence homology with hsa-miR-155, an miRNA frequently found to be up-regulated in lymphomas and critically important for B-cell development. Based on this seed sequence homology, we hypothesized that both miRNAs regulate a common set of target genes and, as a result, could have similar biological activities. Examination of five PEL lines showed that PELs do not express miR-155 but do express high levels of miR-K12-11. Bioinformatic tools predicted the transcriptional repressor BACH-1 to be targeted by both miRNAs, and ectopic expression of either miR-155 or miR-K12-11 inhibited a BACH-1 3'UTR-containing reporter. Furthermore, BACH-1 protein levels are low in cells expressing either miRNA. Gene expression profiling of miRNA-expressing stable cell lines revealed 66 genes that were commonly down-regulated. For select genes, miRNA targeting was confirmed by reporter assays. Thus, based on our in silico predictions, reporter assays, and expression profiling data, miR-K12-11 and miR-155 regulate a common set of cellular targets. Given the role of miR-155 during B-cell maturation, we speculate that miR-K12-11 may contribute to the distinct developmental phenotype of PEL cells, which are blocked in a late stage of B-cell development. Together, these findings indicate that KSHV miR-K12-11 is an ortholog of miR-155.