Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin

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.膜铁转运蛋白（Ferroportin, FPN）是目前已知的哺乳动物细胞中唯一的细胞铁输出蛋白，在维持细胞内及全身铁稳态中发挥关键作用。在铁缺乏状态下，铁调节蛋白（iron regulatory proteins, IRPs）可结合至5'非翻译区（5′ untranslated region, UTR），抑制FPN的翻译过程，从而减少铁输出、留存细胞内铁储备。本研究报道了一种由miR-485-3p介导的全新铁应答性FPN转录后调控机制：miR-485-3p在铁缺乏状态下被诱导表达，并通过直接靶向FPN的3'非翻译区（3′ untranslated region, UTR）抑制FPN的基因表达。过表达miR-485-3p会抑制FPN的表达，使细胞内铁蛋白水平升高，这与细胞内铁含量增加的表型相符。反之，抑制miR-485-3p的活性，或是突变FPN 3'UTR上的miR-485-3p结合位点，均可解除对FPN的抑制，使细胞内铁含量降低。综合上述研究结果，我们提出的调控模型中，IRPs与微小RNA（microRNA）均可作为铁应答性的FPN转录后调控因子。微小RNA参与FPN的铁应答性调控，可为不同细胞环境下的铁稳态提供额外的稳定性保障与精细化调控手段。miR-485-3p介导的FPN抑制机制，或许可为攻克部分由铁调素（hepcidin）抵抗机制引发的铁过载疾病，提供一种全新的潜在治疗策略。