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J Cell Sci. 2015 Sep 1;128(17):3197-209. doi: 10.1242/jcs.165233. Epub 2015 Jul 10.

The miR-199-dynamin regulatory axis controls receptor-mediated endocytosis.

Author information

1
Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06510, USA carlos.fernandez@yale.edu.

Abstract

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.

KEYWORDS:

Endocytosis; LDLR; miR-199; miRNA

PMID:
26163491
PMCID:
PMC4582188
DOI:
10.1242/jcs.165233
[Indexed for MEDLINE]
Free PMC Article

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