The miR-199-dynamin regulatory axis controls receptor-mediated endocytosis
The miR-199-dynamin regulatory axis controls receptor-mediated endocytosis
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DOI：
10.1242/jcs.165233
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发表时间：
2015-09-01
影响因子：
4
通讯作者：
Fernandez-Hernando, Carlos
中科院分区：
文献类型：
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作者：
Aranda, Juan F.;Canfran-Duque, Alberto;Fernandez-Hernando, Carlos
小的非编码RNA（microRNA）是基因表达的重要调节因子，其调节许多生理过程;然而，它们在调节细胞内转运中的作用在很大程度上仍然未知。有趣的是，我们发现动力蛋白（DNM）基因，一个在真核细胞中负责内吞作用的蛋白质的GTdR家族，在其内含子序列中编码保守的miR-199 a和miR-199 b家族的miRNA。在这里，我们证明了miR-199 a和miR-199 b通过控制胞吞作用的重要介质（例如网格蛋白重链（CLTC）、Rab 5A、低密度脂蛋白受体（LDLR）和小窝蛋白-1（Cav-1））的表达来调节胞吞转运。重要的是，miR-199 a-5 p和miR-199 b-5 p过表达显著抑制CLTC、Rab 5A、LDLR和Cav-1表达，从而防止人细胞系（Huh 7和HeLa）中受体介导的内吞作用。值得注意的是，miR-199 a-5 p抑制增加靶基因表达和受体介导的内吞作用。总之，我们的工作确定了一种新的机制，microRNA调节细胞内运输。特别是，我们证明了DNM，miR-199 a-5 p和miR-199 b-5 p基因作为一个双功能基因座，调节内吞作用，从而增加了一个意想不到的层的复杂性，在调节细胞内运输。
Small non-coding RNAs (microRNAs) are important regulators of gene expression that modulate many physiological processes; however, their role in regulating intracellular transport remains largely unknown. Intriguingly, we found that the dynamin (DNM) genes, a GTPase family of proteins responsible for endocytosis in eukaryotic cells, encode the conserved miR-199a and miR-199b family of miRNAs within their intronic sequences. Here, we demonstrate that miR-199a and miR-199b regulate endocytic transport by controlling the expression of important mediators of endocytosis such as clathrin heavy chain (CLTC), Rab5A, low-density lipoprotein receptor (LDLR) and caveolin-1 (Cav-1). Importantly, miR-199a-5p and miR-199b-5p overexpression markedly inhibits CLTC, Rab5A, LDLR and Cav-1 expression, thus preventing receptor-mediated endocytosis in human cell lines (Huh7 and HeLa). Of note, miR-199a-5p inhibition increases target gene expression and receptor-mediated endocytosis. Taken together, our work identifies a new mechanism by which microRNAs regulate intracellular trafficking. In particular, we demonstrate that the DNM, miR-199a-5p and miR-199b-5p genes act as a bifunctional locus that regulates endocytosis, thus adding an unexpected layer of complexity in the regulation of intracellular trafficking.