title: miR-184 regulates ezrin, LAMP-1 expression, affects phagocytosis in human retinal pigment epithelium and is downregulated in age-related macular degeneration.
abstract: MicroRNA 184 (miR-184) is known to play a key role in neurological development and apoptosis and is highly expressed in mouse brain, mouse corneal epithelium, zebrafish lens and human retinal pigment epithelium (RPE). However, the role of miR-184 in RPE is largely unknown. We investigated the role of miR-184 in RPE and its possible implication in age-related macular degeneration (AMD). Proteomic analysis identified the ezrin (EZR) gene as a target of miR-184 in human RPE. EZR is a membrane cytoskeleton crosslinker that is also known to bind to lysosomal-associated membrane protein 1 (LAMP-1) during the formation of phagocytic vacuoles. In adult retinal pigment epithelium 19 (ARPE19) cells, inhibition of miR-184 resulted in upregulation of EZR mRNA and EZR protein, and induced downregulation of LAMP-1. The inhibition of miR-184 decreased EZR-bound LAMP-1 protein levels and affected phagocytic activity in ARPE19 cells. In primary culture of human RPE isolated from eyes of AMD donors (AMD RPE), miR-184 was significantly downregulated compared with control (normal) RPE. Downregulation of miR-184 was consistent with significantly lower levels of LAMP-1 protein in AMD RPE, and overexpression of MIR-184 in AMD RPE was able to rescue LAMP-1 protein expression to normal levels. Altogether, these observations suggest a novel role for miR-184 in RPE health and support a model proposing that downregulation of miR-184 expression during aging may result in dysregulation of RPE function, contributing to retinal degeneration.
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Najiba
authors.initials: N
authors.lastname: Murad
authors.forename: Maria
authors.initials: M
authors.lastname: Kokkinaki
authors.forename: Nishantha
authors.initials: N
authors.lastname: Gunawardena
authors.forename: Mia S
authors.initials: MS
authors.lastname: Gunawan
authors.forename: Yetrib
authors.initials: Y
authors.lastname: Hathout
authors.forename: Karolina J
authors.initials: KJ
authors.lastname: Janczura
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Theos
authors.forename: Nady
authors.initials: N
authors.lastname: Golestaneh
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008268:Macular Degeneration / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D010587:Phagocytosis; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D000099149:Ezrin; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D003598:Cytoskeletal Proteins; D051907:Lysosomal Membrane Proteins; D035683:MicroRNAs; D000099149:Ezrin; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C534424:MIRN184 microRNA, human
keywords: AMD; LAMP-1; RPE; ezrin; miR-184