The miR-199/DNM regulatory axis controls receptor-mediated endocytosis

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/b family of miRNAs within their intronic sequences. Here, we demonstrate that miR-199a/b regulates 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/b-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. Altogether, our work identifies a novel mechanism by which miRNAs regulate intracellular trafficking. In particular, we demonstrate that the DNM/miR-199a/b-5p genes act as a bifunctional locus that regulates endocytosis, thus adding an unexpected layer of complexity in the regulation of intracellular trafficking.