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非经典靶标会使人类AGO蛋白中的微小RNA不稳定。

Non-canonical targets destabilize microRNAs in human Argonautes.

作者信息

Park June Hyun, Shin Sang-Yoon, Shin Chanseok

机构信息

Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea.

Interdisciplinary Program in Agricultural Genomics, Seoul National University, Seoul, 08826, Republic of Korea.

出版信息

Nucleic Acids Res. 2017 Feb 28;45(4):1569-1583. doi: 10.1093/nar/gkx029.

DOI:10.1093/nar/gkx029
PMID:28119422
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5389725/
Abstract

Although much is known about microRNA (miRNA) biogenesis and the mechanism by which miRNAs regulate their targets, little is known about the regulation of miRNA stability. Mature miRNAs are stabilized by binding to Argonaute (Ago) proteins, the core components of the RNA-induced silencing complex (RISC). Recent studies suggest that interactions between miRNAs and their highly complementary target RNAs promote release of miRNAs from Ago proteins, and this in turn can lead to destabilization of miRNAs. However, the physiological triggers of miRNA destabilization with molecular mechanisms remain largely unknown. Here, using an in vitro system that consists of a minimal human Ago2-RISC in HEK293T cell lysates, we sought to understand how miRNAs are destabilized by their targets. Strikingly, we showed that miRNA destabilization is dramatically enhanced by an interaction with seedless, non-canonical targets. We then showed that this process entails not only unloading of miRNAs from Ago, but also 3΄ end destabilization of miRNAs occurred within Ago. Furthermore, our mutation analysis indicates that conformational changes in the hinge region of the Ago PAZ domain are likely to be the main driving force of the miRNA destabilization. Our collective results suggest that non-canonical targets may provide a stability control mechanism in the regulation of miRNAs in humans.

摘要

尽管人们对微小RNA（miRNA）的生物合成以及miRNA调控其靶标的机制了解颇多，但对于miRNA稳定性的调控却知之甚少。成熟的miRNA通过与RNA诱导沉默复合体（RISC）的核心组分AGO蛋白结合而得以稳定。最近的研究表明，miRNA与其高度互补的靶RNA之间的相互作用会促使miRNA从AGO蛋白上释放，进而可能导致miRNA的不稳定。然而，miRNA不稳定的生理触发因素及其分子机制在很大程度上仍不清楚。在此，我们利用一个由HEK293T细胞裂解物中的最小化人AGO2-RISC组成的体外系统，试图了解miRNA如何被其靶标 destabilized。令人惊讶的是，我们发现与无种子、非经典靶标的相互作用会显著增强miRNA的destabilization。随后我们表明，这一过程不仅涉及miRNA从AGO上卸载，还涉及AGO内miRNA的3΄端destabilization。此外，我们的突变分析表明，AGO PAZ结构域铰链区的构象变化可能是miRNA destabilization的主要驱动力。我们的研究结果共同表明，非经典靶标可能在人类miRNA的调控中提供一种稳定性控制机制。 （注：原文中destabilized未找到合适中文对应词，暂保留英文）

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/a8baf50f3b9f/gkx029fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/25c036db9680/gkx029fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/6e1452330e24/gkx029fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/b004b6b4f3a4/gkx029fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/5d3da1d3b275/gkx029fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/c30cc2c991d7/gkx029fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/15e1ed43b815/gkx029fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/f1e3655ad04a/gkx029fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/a8baf50f3b9f/gkx029fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/25c036db9680/gkx029fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/6e1452330e24/gkx029fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/b004b6b4f3a4/gkx029fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/5d3da1d3b275/gkx029fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/c30cc2c991d7/gkx029fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/15e1ed43b815/gkx029fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/f1e3655ad04a/gkx029fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ebf/5389725/a8baf50f3b9f/gkx029fig8.jpg

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