title: Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin.
abstract: Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5' untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-responsive mechanism for the post-transcriptional regulation of FPN, mediated by miR-485-3p, which is induced during iron deficiency and represses FPN expression by directly targeting the FPN 3'UTR. The overexpression of miR-485-3p represses FPN expression and leads to increased cellular ferritin levels, consistent with increased cellular iron. Conversely, both inhibition of miR-485-3p activity and mutation of the miR-485-3p target sites on the FPN 3'UTR are able to relieve FPN repression and lead to decreased cellular iron levels. Together, these findings support a model that includes both IRPs and microRNAs as iron-responsive post-transcriptional regulators of FPN. The involvement of microRNA in the iron-responsive regulation of FPN offers additional stability and fine-tuning of iron homeostasis within different cellular contexts. MiR-485-3p-mediated repression of FPN may also offer a novel potential therapeutic mechanism for circumventing hepcidin-resistant mechanisms responsible for some iron overload diseases.
authors.affiliation: The Institute for Genome Sciences and Policy, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sangokoya
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Doss
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D035925:Iron-Regulatory Proteins; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D000098742:Ferroportin; D007501:Iron