Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation.
Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation.
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DOI：
10.1091/mbc.e12-09-0648
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发表时间：
2013-06
影响因子：
3.3
通讯作者：
Lillig CH
中科院分区：
文献类型：
--
作者：
Haunhorst P;Hanschmann EM;Bräutigam L;Stehling O;Hoffmann B;Mühlenhoff U;Lill R;Berndt C;Lillig CH
脊椎动物glutaredoxin 3 （PICOT）通过其在铁稳态中的基本功能对血红蛋白血红素辅助因子的成熟至关重要。这些数据表明细胞质单硫醇多结构域Grxs在细胞铁代谢途径中的进化保守作用。真核细胞在细胞质和其他细胞区室中处理和分配必需微量营养素铁的机制才刚刚开始出现。酵母单硫醇多结构域glutaredoxins (Grx) 3和4对铁的转录调控和细胞内铁的分布都是必不可少的。尽管真菌和高等真核生物的铁代谢机制存在巨大差异，但glutaredoxins是保守的，但它们在脊椎动物中的确切功能仍然难以捉摸。在这里，我们证明了脊椎动物特异性单硫醇多域Grx3 （PICOT）在细胞铁稳态中的关键作用。在斑马鱼胚胎发育过程中，Grx3的缺失严重损害了血红蛋白的成熟，而血红蛋白是主要的铁消耗过程。在HeLa细胞中，沉默人Grx3的表达会降低几种胞质铁/硫蛋白的活性，例如铁调控蛋白1，它是铁转录后调控的主要成分。因此，grx3耗尽的细胞表现出铁蛋白水平下降和转铁蛋白受体水平升高，这是细胞铁饥饿的特征。显然，缺乏grx3的细胞不能有效地利用铁，尽管细胞铁摄取未受损。这些数据表明，胞质单硫醇多结构域glutaredoxins在细胞铁代谢途径（包括铁/硫蛋白的生物发生和血红蛋白成熟）中具有进化保守的作用。
Vertebrate glutaredoxin 3 (PICOT) is essential for the maturation of the heme cofactor of hemoglobin through its essential functions in iron homeostasis. The data suggest an evolutionarily conserved role of cytosolic monothiol multidomain Grxs in cellular iron metabolism pathways. The mechanisms by which eukaryotic cells handle and distribute the essential micronutrient iron within the cytosol and other cellular compartments are only beginning to emerge. The yeast monothiol multidomain glutaredoxins (Grx) 3 and 4 are essential for both transcriptional iron regulation and intracellular iron distribution. Despite the fact that the mechanisms of iron metabolism differ drastically in fungi and higher eukaryotes, the glutaredoxins are conserved, yet their precise function in vertebrates has remained elusive. Here we demonstrate a crucial role of the vertebrate-specific monothiol multidomain Grx3 (PICOT) in cellular iron homeostasis. During zebrafish embryonic development, depletion of Grx3 severely impairs the maturation of hemoglobin, the major iron-consuming process. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe/S proteins, for example, iron-regulatory protein 1, a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation. Apparently, Grx3-deficient cells are unable to efficiently use iron, despite unimpaired cellular iron uptake. These data suggest an evolutionarily conserved role of cytosolic monothiol multidomain glutaredoxins in cellular iron metabolism pathways, including the biogenesis of Fe/S proteins and hemoglobin maturation.