Iron-regulatory protein 1 (IRP1), a central regulator of iron metabolism in vertebrates, also affects cellular response to hypoxia. IRP1 binds to the iron-responsive element (IRE) in the mRNA encoding hypoxia-inducible factor (HIF) 2α, thereby blocking the translation of the HIF2α-mRNA, and allowing the transcriptional regulation of, e.g., erythropoiesis. Here, we characterize the oxidoreductase thioredoxin 1 (Trx1) as a new regulator of hypoxia signaling. Human and murine Trx1 complex iron-sulfur clusters using one of the active site cysteinyl residues and a vertebrate-specific additional cysteinyl residue outside the active site. FeS-Trx1 is inactive, activated apo-Trx1 reduces cysteinyl residues in the binding pocket of IRP1/apo-Aconitase 1, which allows IRP1 to bind IREs in regulated mRNAs. Therefore, translation of the HIF2α mRNA requires either sufficient iron supply or the lack of reducing power of the Trx system under iron-limiting conditions. FeS-Trx1 thus links both redox and iron homeostasis to hypoxia responses.

中文翻译：

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脊椎动物硫氧还蛋白的 FeS 簇协调通过铁调节蛋白 1 调节缺氧诱导因子 2α 的抑制

铁调节蛋白 1 (IRP1) 是脊椎动物铁代谢的中心调节因子，也会影响细胞对缺氧的反应。IRP1与编码缺氧诱导因子(HIF)2α的mRNA中的铁反应元件(IRE)结合，从而阻断HIF2α-mRNA的翻译，并允许例如红细胞生成的转录调节。在这里，我们将氧化还原酶硫氧还蛋白 1 (Trx1) 描述为缺氧信号传导的新调节剂。人类和鼠类 Trx1 复合物铁硫簇使用活性位点半胱氨酰残基之一和活性位点外的脊椎动物特异性附加半胱氨酰残基。FeS-Trx1 是无活性的，激活的 apo-Trx1 会减少 IRP1/apo-Aconitase 1 结合口袋中的半胱氨酰残基，从而使 IRP1 能够结合受调节 mRNA 中的 IRE。因此，HIF2α mRNA 的翻译需要足够的铁供应，或者在铁限制条件下缺乏 Trx 系统的还原能力。因此，FeS-Trx1 将氧化还原和铁稳态与缺氧反应联系起来。