The actin-binding protein profilin 2 is a novel regulator of iron homeostasis.
The actin-binding protein profilin 2 is a novel regulator of iron homeostasis.
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DOI：
10.1182/blood-2016-11-754382
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发表时间：
2017-10
期刊：
影响因子：
20.3
通讯作者：
Sara Luscieti;B. Galy;Lucía Gutiérrez;Michael Reinke;J. Couso;Maya Shvartsman;Antonio Di Pascale;W. Witke;M. Hentze;Pietro Pilo Boyl;Mayka Sánchez
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文献类型：
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作者：
Sara Luscieti;B. Galy;Lucía Gutiérrez;Michael Reinke;J. Couso;Maya Shvartsman;Antonio Di Pascale;W. Witke;M. Hentze;Pietro Pilo Boyl;Mayka Sánchez
细胞铁稳态是由铁调节蛋白(IRPS)1和2控制的，它们将顺式调节的铁反应元件(IRE)结合到靶信使RNA(MRNA)上。我们鉴定了Profilin 2(Pfn2)mRNA，它编码一种肌动蛋白结合蛋白，参与内吞作用和神经递质的释放，是一种新的IRP相互作用转录本，并研究了它在铁代谢中的作用。结合电泳迁移率改变实验和生物信息学分析，在Pfn2mRNA的3‘非翻译区发现了一个非典型和保守的IRE。肠IRP消融小鼠十二指肠组织中Pfn2基因表达水平显著降低，提示IRPS对体内Pfn2基因表达有正向影响。Pfn2在HeLa和Hepa1-6细胞中的过表达减少了它们的代谢活性铁库。重要的是，Pfn2基因缺陷的小鼠在大脑的不同区域(嗅球、海马体和中脑)表现出铁的积累，并在没有贫血的情况下减少了肝脏铁的储存。尽管肝脏铁水平较低，但肝脏海普西丁的表达仍然很高，这可能是由于轻微炎症对海普西丁的代偿激活。脾组织铁蛋白升高可能是为了维持造血功能。总之，我们的结果表明，Pfn2在体内的表达受IRPS的控制，并且Pfn2有助于维持细胞系和小鼠的铁稳态。
Cellular iron homeostasis is controlled by the iron regulatory proteins (IRPs) 1 and 2 that bind cis-regulatory iron-responsive elements (IRE) on target messenger RNAs (mRNA). We identified profilin 2 (Pfn2) mRNA, which encodes an actin-binding protein involved in endocytosis and neurotransmitter release, as a novel IRP-interacting transcript, and studied its role in iron metabolism. A combination of electrophoretic mobility shift assay experiments and bioinformatic analyses led to the identification of an atypical and conserved IRE in the 3' untranslated region of Pfn2 mRNA. Pfn2 mRNA levels were significantly reduced in duodenal samples from mice with intestinal IRP ablation, suggesting that IRPs exert a positive effect on Pfn2 mRNA expression in vivo. Overexpression of Pfn2 in HeLa and Hepa1-6 cells reduced their metabolically active iron pool. Importantly, Pfn2-deficient mice showed iron accumulation in discrete areas of the brain (olfactory bulb, hippocampus, and midbrain) and reduction of the hepatic iron store without anemia. Despite low liver iron levels, hepatic hepcidin expression remained high, likely because of compensatory activation of hepcidin by mild inflammation. Splenic ferroportin was increased probably to sustain hematopoiesis. Overall, our results indicate that Pfn2 expression is controlled by the IRPs in vivo and that Pfn2 contributes to maintaining iron homeostasis in cell lines and mice.