Ghosh Manik C, Tong Wing-Hang, Zhang Deliang, Ollivierre-Wilson Hayden, Singh Anamika, Krishna Murali C, Mitchell James B, Rouault Tracey A
National Institute of Child Health and Human Development and Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12028-33. doi: 10.1073/pnas.0805361105. Epub 2008 Aug 6.
In mammals, two homologous cytosolic regulatory proteins, iron regulatory protein 1 (also known as IRP1 and Aco1) and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttranscriptionally regulate iron metabolism genes, including transferrin receptor 1 (TfR1) and ferritin H and L subunits, by binding to iron-responsive elements (IREs) within target transcripts. Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression. IRP1 knockout (IRP1(-/-)) animals do not significantly misregulate iron metabolism, partly because IRP1 is an iron-sulfur protein that functions mainly as a cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IRE binding form of IRP1. The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age. In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated. In cell lines derived from IRP2(-/-) animals, and in the cerebellum, brainstem, and forebrain of animals maintained on the Tempol diet, IRP1 was converted from a cytosolic aconitase to an IRE binding protein that stabilized the TfR1 transcript and repressed ferritin synthesis. We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain.
在哺乳动物中，两种同源的胞质调节蛋白，即铁调节蛋白1（也称为IRP1和Aco1）和铁调节蛋白2（也称为IRP2和Ireb2），可感知胞质铁水平，并通过与靶转录本中的铁反应元件（IRE）结合，在转录后调节铁代谢基因，包括转铁蛋白受体1（TfR1）以及铁蛋白H和L亚基。缺乏IRP2的小鼠会出现小细胞性贫血和神经退行性变，这与低TfR1和高铁蛋白表达导致的功能性细胞铁耗竭有关。IRP1基因敲除（IRP1(-/-)）动物的铁代谢并未出现明显失调，部分原因是IRP1是一种铁硫蛋白，在哺乳动物组织中主要作为胞质乌头酸酶发挥作用，而IRP2的活性会增加以补偿IRP1的IRE结合形式的缺失。随着年龄增长，IRP2(-/-)动物的神经退行性疾病进展缓慢。在本研究中，我们给IRP2(-/-)小鼠喂食添加了稳定氮氧化物Tempol的饮食，结果显示神经肌肉损伤的进展明显减缓。在源自IRP2(-/-)动物的细胞系以及食用Tempol饮食的动物的小脑、脑干和前脑中，IRP1从胞质乌头酸酶转变为IRE结合蛋白，从而稳定了TfR1转录本并抑制了铁蛋白合成。我们认为，Tempol通过拆解IRP1的胞质铁硫簇并激活IRE结合活性来保护IRP2(-/-)小鼠，这稳定了TfR1转录本，抑制了铁蛋白合成，并部分恢复了大脑中正常的细胞铁稳态。
