Lineberger Comprehensive Cancer Center and Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):941-6. doi: 10.1073/pnas.1112263109. Epub 2012 Jan 3.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate eukaryotic gene expression by binding to regions of imperfect complementarity in mRNAs, typically in the 3' UTR, recruiting an Argonaute (Ago) protein complex that usually results in translational repression or destabilization of the target RNA. The translation and decay of mRNAs are closely linked, competing processes, and whether the miRNA-induced silencing complex (RISC) acts primarily to reduce translation or stability of the mRNA remains controversial. miR-122 is an abundant, liver-specific miRNA that is an unusual host factor for hepatitis C virus (HCV), an important cause of liver disease in humans. Prior studies show that it binds the 5' UTR of the messenger-sense HCV RNA genome, stimulating translation and promoting genome replication by an unknown mechanism. Here we show that miR-122 binds HCV RNA in association with Ago2 and that this slows decay of the viral genome in infected cells. The stabilizing action of miR-122 does not require the viral RNA to be translationally active nor engaged in replication, and can be functionally substituted by a nonmethylated 5' cap. Our data demonstrate that a RISC-like complex mediates the stability of HCV RNA and suggest that Ago2 and miR-122 act coordinately to protect the viral genome from 5' exonuclease activity of the host mRNA decay machinery. miR-122 thus acts in an unconventional fashion to stabilize HCV RNA and slow its decay, expanding the repertoire of mechanisms by which miRNAs modulate gene expression.
微小 RNA（miRNAs）是小的非编码 RNA，通过与 mRNAs 中的不完全互补区域（通常在 3'UTR 中）结合，招募 Argonaute（Ago）蛋白复合物来调节真核生物基因表达，通常导致靶 RNA 的翻译抑制或不稳定。mRNA 的翻译和衰减是密切相关的竞争过程，miRNA 诱导的沉默复合物（RISC）主要作用是降低翻译还是 mRNA 的稳定性仍然存在争议。miR-122 是一种丰富的、肝脏特异性的 miRNA，是丙型肝炎病毒（HCV）的一个不寻常的宿主因子，是人类肝脏疾病的重要原因。先前的研究表明，它与 HCV 信使 sense RNA 基因组的 5'UTR 结合，通过未知的机制刺激翻译并促进基因组复制。在这里，我们表明 miR-122 与 Ago2 结合结合 HCV RNA，这会减缓感染细胞中病毒基因组的衰减。miR-122 的稳定作用不需要病毒 RNA 具有翻译活性或参与复制，并且可以通过非甲基化的 5'帽来进行功能替代。我们的数据表明，一种类似于 RISC 的复合物介导了 HCV RNA 的稳定性，并表明 Ago2 和 miR-122 协同作用以保护病毒基因组免受宿主 mRNA 衰减机制的 5'外切酶活性的影响。miR-122 因此以一种非传统的方式稳定 HCV RNA 并减缓其衰减，扩展了 miRNAs 调节基因表达的机制谱。
