Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
Biochem Biophys Res Commun. 2019 Apr 2;511(2):422-426. doi: 10.1016/j.bbrc.2019.02.075. Epub 2019 Feb 21.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at post-transcriptional level via translational repression and/or mRNA degradation. miRNAs are associated with many cellular processes, and down-regulation of miRNAs causes numerous diseases including cancer, neurological disorders, inflammation, and cardiovascular diseases, for which miRNA replacement therapy has emerged as a promising approach. This approach aims to restore down-regulated miRNAs using synthetic miRNA mimics. However, it remains a critical issue that miRNA mimics are unstable and transient in cells. Here, we first show that miRNA mimics are rapidly degraded by a mechanism different from Tudor-staphylococcal/micrococcal-like nuclease (TSN)-mediated miRNA decay, which degrades endogenous miRNAs, and newly identified 2'-5'-oligoadenylate synthetase (OAS)/RNase L as key factors responsible for the degradation of miRNA mimics in human cells. Our results suggest that the OAS1 recognizes miRNA mimics and produces 2'-5'-oligoadenylates (2-5A), which leads to the activation of latent endoribonuclease RNase L to degrade miRNA mimics. A small-molecule inhibitor that blocks RNase L can stabilize miRNA mimics. These findings provide a promising method for the stabilization of miRNA mimics, as well as for the efficient miRNA replacement therapy.
微小 RNA（miRNAs）是一类小的非编码 RNA，通过翻译抑制和/或 mRNA 降解在转录后水平负调控基因表达。miRNAs 与许多细胞过程有关，miRNAs 的下调导致许多疾病，包括癌症、神经紊乱、炎症和心血管疾病，为此，miRNA 替代疗法已成为一种很有前途的方法。该方法旨在使用合成 miRNA 模拟物来恢复下调的 miRNA。然而，miRNA 模拟物在细胞中不稳定和短暂仍然是一个关键问题。在这里，我们首先表明，miRNA 模拟物通过不同于 Tudor-葡萄球菌/微球菌样核酸内切酶（TSN）介导的 miRNA 降解的机制迅速降解，后者降解内源性 miRNAs，而新鉴定的 2'-5'-寡聚腺苷酸合成酶（OAS）/核糖核酸酶 L 是负责 miRNA 模拟物在人细胞中降解的关键因素。我们的结果表明，OAS1 识别 miRNA 模拟物并产生 2'-5'-寡聚腺苷酸（2-5A），这导致潜伏的内切核糖核酸酶核糖核酸酶 L 的激活以降解 miRNA 模拟物。一种阻断核糖核酸酶 L 的小分子抑制剂可以稳定 miRNA 模拟物。这些发现为 miRNA 模拟物的稳定以及有效的 miRNA 替代疗法提供了一种很有前途的方法。
