title: The miR-199-dynamin 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 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.
authors.affiliation: 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.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Aranda
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Canfrán-Duque
authors.affiliation: 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.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.affiliation: 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.
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000818:Animals; D019556:COS Cells; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D033922:Clathrin Heavy Chains / Q000235:genetics / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D035683:MicroRNAs; C531408:mirn199 microRNA, human; D033922:Clathrin Heavy Chains; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins; D034281:Dynamins
keywords: Endocytosis; LDLR; miR-199; miRNA