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.
Highlights
While iron is an essential nutrient for all cells, high levels of iron can lead to toxicity
Cellular iron homeostasis is maintained by a sophisticated system that responds to iron levels and coordinates the expression of targets important for balancing iron export and uptake with intracellular storage and utilization
The ability to regulate cellular iron export is of great interest in the search for therapeutic strategies to control dysregulated iron homeostasis, iron overload disorders, and conditions affected by cellular iron concentrations such as antimicrobial resistance
Summary
While iron is an essential nutrient for all cells, high levels of iron can lead to toxicity. Cellular iron homeostasis is carefully maintained by an exquisite system of iron regulatory proteins (IRPs) that respond to iron levels and coordinate the expression of targets important for balancing iron export and uptake with intracellular storage and utilization [1,2]. Ferroportin (FPN) functions as the only known iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance [3,4,5]. IRPs inhibit the translation of FPN by binding to the iron regulatory element (IRE) located in the 59 untranslated region (UTR) of FPN messenger RNA (mRNA), leading to lower FPN protein levels, decreased export of iron, and cellular iron retention [11]. Hepcidin targets membrane-bound FPN for degradation and decreases FPN-mediated iron export
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