Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin.
Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin.
复制标题
DOI：
10.1371/journal.pgen.1003408
复制
发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
Sangokoya C;Doss JF;Chi JT
膜铁转运蛋白（FPN）是哺乳动物细胞中唯一已知的细胞铁输出蛋白，在维持细胞和全身铁平衡中起着关键作用。在铁剥夺过程中，FPN的翻译被铁调节蛋白（IRP）抑制，IRP与5′非翻译区（UTR）结合，以减少铁输出并保护细胞铁。在这里，我们报告了一种新的铁反应机制，FPN的转录后调控，由miR-485- 3 p介导，这是诱导在缺铁和抑制FPN的表达直接针对FPN的3′UTR。miR-485- 3 p的过表达抑制FPN表达并导致细胞铁蛋白水平增加，与细胞铁增加一致。相反，抑制miR-485- 3 p活性和FPN 3′UTR上miR-485- 3 p靶位点的突变都能够缓解FPN抑制并导致细胞铁水平降低。总之，这些发现支持了一个模型，该模型包括IRP和microRNA作为FPN的铁响应性转录后调节因子。microRNA参与FPN的铁响应性调节提供了不同细胞环境中铁稳态的额外稳定性和微调。miR-485- 3 p介导的FPN抑制也可能提供一种新的潜在治疗机制，用于规避导致某些铁过载疾病的铁调素耐药机制。细胞铁稳态由一个复杂的系统维持，该系统响应铁水平并协调对平衡铁输出和吸收与细胞内储存和利用重要的靶点的表达。膜铁转运蛋白是哺乳动物细胞中唯一已知的细胞铁输出蛋白，在细胞和全身铁平衡中起关键作用。因此，调节细胞铁输出的能力在寻找治疗策略以控制失调的铁稳态、铁超负荷病症和受细胞铁浓度影响的病症（如抗微生物剂抗性）方面具有极大的兴趣。在缺铁期间，膜铁转运蛋白水平的抑制减少铁输出并保存细胞铁。膜铁转运蛋白的翻译被与5′UTR结合的铁调节蛋白所抑制，但转录后调节膜铁转运蛋白的其他机制尚未报道。在这里，我们发现miR-485- 3 p在缺铁时被诱导，并通过直接靶向其3′UTR来抑制膜铁转运蛋白，进一步的实验证据支持了一个模型，该模型包括铁调节蛋白和microRNA作为膜铁转运蛋白的转录后调节因子。这些发现证明了microRNA在细胞对铁缺乏的反应中的新作用，并且可以对各种铁稳态疾病具有治疗意义。
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. 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. Ferroportin is the only known cellular iron exporter in mammalian cells and plays a critical role in both cellular and systemic iron balance. Thus 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. During iron deprivation, repression of ferroportin levels reduces iron export and preserves cellular iron. Ferroportin translation is known to be repressed by iron regulatory proteins that bind to the 5′UTR, yet alternative mechanisms that can post-transcriptionally regulate ferroportin have not been previously reported. Here, we find that miR-485-3p is induced during iron deficiency and represses ferroportin by directly targeting its 3′UTR, and further experimental evidence supports a model that includes both iron regulatory proteins and microRNAs as post-transcriptional regulators of ferroportin. These findings demonstrate a novel role for microRNAs in the cellular response to iron deficiency and can have therapeutic implications for various diseases of iron homeostasis.
登录
查看更多内容
影响因子：
--
作者：
Barton, James C
通讯作者：
Barton, James C
影响因子：
16
作者：
Leung AK;Sharp PA
通讯作者：
Sharp PA
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
20.3
作者：
Drakesmith, H;Schimanski, LM;Townsend, ARM
通讯作者：
Townsend, ARM
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC