An iron responsive element-like stem-loop regulates α-hemoglobin-stabilizing protein mRNA
An iron responsive element-like stem-loop regulates α-hemoglobin-stabilizing protein mRNA
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DOI：
10.1074/jbc.m802421200
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发表时间：
2008-10-03
影响因子：
4.8
通讯作者：
Weiss, Mitchell J.
中科院分区：
文献类型：
--
作者：
dos Santos, Camila O.;Dore, Louis C.;Weiss, Mitchell J.
红细胞生成过程中血红蛋白的产生与铁的获得和代谢机械耦合。我们发现铁调节α-血红蛋白稳定蛋白（AHSP）的表达，AHSP是一种在血红蛋白合成过程中结合并稳定游离α-珠蛋白的分子伴侣。在灵长类动物中，α-血红蛋白稳定蛋白mRNA的3 '-非翻译区（UTR）含有类似于铁反应元件（IRE）的核苷酸序列，IRE是通过结合铁调节蛋白（IRP）在转录后调节基因表达的茎环结构。血红蛋白稳定蛋白IRE样茎环偏离经典的共有序列，在电泳迁移率变化试验中与IRP结合较差。然而，在细胞质提取物中，α-血红蛋白稳定蛋白mRNA与IRP以一种依赖于茎环结构并被铁抑制的方式共免疫沉淀。此外，这种相互作用增强了血红蛋白稳定蛋白mRNA在红系和异源细胞中的稳定性。我们的研究结果表明，IRP可以通过非经典的IRES调节mRNA的表达，并扩展了已知的铁调节基因的库。此外，我们说明了一种新的机制，通过该机制血红蛋白可能会根据铁的状态进行调制。
Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of alpha-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free alpha-globin during hemoglobin synthesis. In primates, the 3 '-untranslated region (UTR) of AHSP mRNA contains a nucleotide sequence resembling iron responsive elements (IREs), stem-loop structures that regulate gene expression post-transcriptionally by binding iron regulatory proteins (IRPs). The AHSP IRE-like stem-loop deviates from classical consensus sequences and binds IRPs poorly in electrophoretic mobility shift assays. However, in cytoplasmic extracts, AHSP mRNA co-immunoprecipitates with IRPs in a fashion that is dependent on the stem-loop structure and inhibited by iron. Moreover, this interaction enhances AHSP mRNA stability in erythroid and heterologous cells. Our findings demonstrate that IRPs can regulate mRNA expression through non-canonical IREs and extend the repertoire of known iron-regulated genes. In addition, we illustrate a new mechanism through which hemoglobin may be modulated according to iron status.