Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster
Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster
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DOI：
10.1038/sj.emboj.7600954
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发表时间：
2006-02-08
期刊：
影响因子：
11.4
通讯作者：
Eisenstein, RS
中科院分区：
文献类型：
--
作者：
Clarke, SL;Vasanthakumar, A;Eisenstein, RS
铁调节蛋白1（IRP 1）在协调铁调节的mRNA的命运中的普遍接受的作用取决于其胞质乌头酸酶和RNA结合形式通过其Fe-S簇的组装/拆卸的相互转化，而不改变蛋白质丰度。在这里，我们表明，IRP 1蛋白丰度可以铁调节。铁对IRP 1丰度的调节不需要组装Fe-S簇，因为所有簇连接半胱氨酸突变为丝氨酸的突变体经历了铁诱导的蛋白质降解。IRP 1在S138处的磷酸化有利于RNA结合形式并促进铁依赖性降解。然而，S138的磷酸化不是降解所必需的。此外，S138磷酸模拟突变体的降解没有被簇连接半胱氨酸的突变阻断。这些发现在具有细胞溶质Fe-S簇组装/分解中的遗传缺陷的小鼠模型中得到证实。在这些动物中，IRP 1 RNA结合活性主要由IRP 1降解调节。我们的研究结果揭示了一种调节IRP 1作用的机制，该机制与细胞增殖、炎症以及对改变胞质Fe-S簇组装或分解的疾病的反应中的铁稳态控制有关。
The generally accepted role of iron-regulatory protein 1 (IRP1) in orchestrating the fate of iron-regulated mRNAs depends on the interconversion of its cytosolic aconitase and RNA-binding forms through assembly/ disassembly of its Fe - S cluster, without altering protein abundance. Here, we show that IRP1 protein abundance can be iron-regulated. Modulation of IRP1 abundance by iron did not require assembly of the Fe - S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation. Phosphorylation of IRP1 at S138 favored the RNA-binding form and promoted iron-dependent degradation. However, phosphorylation at S138 was not required for degradation. Further, degradation of an S138 phosphomimetic mutant was not blocked by mutation of cluster-ligating cysteines. These findings were confirmed in mouse models with genetic defects in cytosolic Fe - S cluster assembly/ disassembly. IRP1 RNA-binding activity was primarily regulated by IRP1 degradation in these animals. Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe - S cluster assembly or disassembly.