Mature microRNA-binding protein QKI promotes microRNA-mediated gene silencing.

IF 3.6 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RNA Biology Pub Date : 2024-01-01 Epub Date: 2024-02-19 DOI:10.1080/15476286.2024.2314846
Kyung-Won Min, Myung Hyun Jo, Minseok Song, Ji Won Lee, Min Ji Shim, Kyungmin Kim, Hyun Bong Park, Shinwon Ha, Hyejin Mun, Ahsan Polash, Markus Hafner, Jung-Hyun Cho, Dongsan Kim, Ji-Hoon Jeong, Seungbeom Ko, Sungchul Hohng, Sung-Ung Kang, Je-Hyun Yoon
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Abstract

Although Argonaute (AGO) proteins have been the focus of microRNA (miRNA) studies, we observed AGO-free mature miRNAs directly interacting with RNA-binding proteins, implying the sophisticated nature of fine-tuning gene regulation by miRNAs. To investigate microRNA-binding proteins (miRBPs) globally, we analyzed PAR-CLIP data sets to identify RBP quaking (QKI) as a novel miRBP for let-7b. Potential existence of AGO-free miRNAs were further verified by measuring miRNA levels in genetically engineered AGO-depleted human and mouse cells. We have shown that QKI regulates miRNA-mediated gene silencing at multiple steps, and collectively serves as an auxiliary factor empowering AGO2/let-7b-mediated gene silencing. Depletion of QKI decreases interaction of AGO2 with let-7b and target mRNA, consequently controlling target mRNA decay. This finding indicates that QKI is a complementary factor in miRNA-mediated mRNA decay. QKI, however, also suppresses the dissociation of let-7b from AGO2, and slows the assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. We also revealed that QKI overexpression suppresses cMYC expression at post-transcriptional level, and decreases proliferation and migration of HeLa cells, demonstrating that QKI is a tumour suppressor gene by in part augmenting let-7b activity. Our data show that QKI is a new type of RBP implicated in the versatile regulation of miRNA-mediated gene silencing.

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成熟的 microRNA 结合蛋白 QKI 可促进 microRNA 介导的基因沉默。
尽管Argonaute(AGO)蛋白一直是microRNA(miRNA)研究的重点,但我们观察到不含AGO的成熟miRNA直接与RNA结合蛋白相互作用,这意味着miRNA微调基因调控的复杂性。为了在全球范围内研究microRNA结合蛋白(miRBPs),我们分析了PAR-CLIP数据集,发现RBP quaking(QKI)是let-7b的新型miRBP。通过测量基因工程AGO缺失的人类和小鼠细胞中的miRNA水平,进一步验证了不含AGO的miRNA的潜在存在。我们的研究表明,QKI 在多个步骤上调控 miRNA 介导的基因沉默,并共同作为辅助因子赋予 AGO2/let-7b 介导的基因沉默权力。消耗 QKI 会减少 AGO2 与 let-7b 和目的 mRNA 的相互作用,从而控制目的 mRNA 的衰变。这一发现表明,QKI 是 miRNA 介导的 mRNA 衰减过程中的一个互补因子。然而,QKI 也抑制了 let-7b 与 AGO2 的解离,并在单分子水平上减缓了 AGO2/miRNA/ 目标 mRNA 复合物的组装。我们还发现,QKI 的过表达在转录后水平抑制了 cMYC 的表达,并降低了 HeLa 细胞的增殖和迁移,这表明 QKI 在一定程度上增强了 let-7b 的活性,是一种肿瘤抑制基因。我们的数据表明,QKI 是一种新型 RBP,与 miRNA 介导的基因沉默的多功能调控有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
RNA Biology
RNA Biology 生物-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
82
审稿时长
1 months
期刊介绍: RNA has played a central role in all cellular processes since the beginning of life: decoding the genome, regulating gene expression, mediating molecular interactions, catalyzing chemical reactions. RNA Biology, as a leading journal in the field, provides a platform for presenting and discussing cutting-edge RNA research. RNA Biology brings together a multidisciplinary community of scientists working in the areas of: Transcription and splicing Post-transcriptional regulation of gene expression Non-coding RNAs RNA localization Translation and catalysis by RNA Structural biology Bioinformatics RNA in disease and therapy
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