Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
FEBS Lett. 2011 Feb 18;585(4):687-92. doi: 10.1016/j.febslet.2011.01.036. Epub 2011 Feb 1.
Iron regulatory protein 2 (IRP2) is a critical switch for cellular and systemic iron homeostasis. In iron-deficient or hypoxic cells, IRP2 binds to mRNAs containing iron responsive elements (IREs) and regulates their expression. Iron promotes proteasomal degradation of IRP2 via the F-box protein FBXL5. Here, we explored the effects of oxygen and cellular redox status on IRP2 stability. We show that iron-dependent decay of tetracycline-inducible IRP2 proceeds efficiently under mild hypoxic conditions (3% oxygen) but is compromised in severe hypoxia (0.1% oxygen). A treatment of cells with exogenous H(2)O(2) protects IRP2 against iron and increases its IRE-binding activity. IRP2 is also stabilized during menadione-induced oxidative stress. These data demonstrate that the degradation of IRP2 in iron-replete cells is not only oxygen-dependent but also sensitive to redox perturbations.
铁调节蛋白 2（IRP2）是细胞和全身铁稳态的关键开关。在缺铁或缺氧的细胞中，IRP2 结合含有铁反应元件（IRE）的 mRNA，并调节其表达。铁通过 F-box 蛋白 FBXL5 促进 IRP2 的蛋白酶体降解。在这里，我们探讨了氧和细胞氧化还原状态对 IRP2 稳定性的影响。我们表明，在轻度低氧条件（3%氧气）下，四环素诱导的 IRP2 的铁依赖性衰减过程效率很高，但在严重缺氧（0.1%氧气）下受到损害。用外源性 H2O2 处理细胞可保护 IRP2 免受铁的侵害，并增加其 IRE 结合活性。IRP2 在甲萘醌诱导的氧化应激期间也得到稳定。这些数据表明，铁充足细胞中 IRP2 的降解不仅依赖于氧，而且对氧化还原波动敏感。
