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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons
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Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons

机译:Ndfip1调节二价金属转运蛋白1(DMT1)可防止金属对人类神经元的毒性

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摘要

The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4-2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1~(-/-) with Nd-fip1~(+/+) mice exposed to Fe reveals that Ndfip1~(-/-) brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.
机译:神经元内金属离子运输的调节对于正常的大脑功能至关重要。尤其重要的是调节氧化还原金属,例如铁(Fe),其中过量的金属会导致氧化应激和蛋白质聚集,从而导致神经元死亡。二价金属转运体1(DMT1)在调节Fe和其他金属方面起着核心作用;因此,DMT1调控的失败与人脑病理学有关。但是,尚不清楚DMT1在大脑中如何被调节。在这里,我们显示DMT1受Ndfip1(Nedd4家族相互作用蛋白1)调控,Ndfip1是一种募集E3连接酶以泛素化靶蛋白的衔接蛋白。使用人类神经元,我们显示Ndfip1被上调并与DMT1结合,以响应铁和钴(Co)暴露。这种相互作用导致DMT1的泛素化和降解,从而减少了金属的进入。 Ndfip1表达的诱导保护神经元免受金属毒性,shRNAi去除Ndfip1导致对金属过敏。我们确定Nedd4-2为Ndfip1募集的E3连接酶,用于人类神经元内DMT1的泛素化。将Ndfip1〜(-/-)与暴露于Fe的Nd-fip1〜(+ / +)小鼠的大脑进行比较,发现Ndfip1〜(-/-)大脑在神经元内积累了Fe。总之,这一证据表明Ndfip1在调节人类神经元中的金属运输中起着至关重要的作用。

著录项

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  • 作者单位

    Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia;

    Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia;

    Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia;

    Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia;

    Center for Cancer Biology, SA Pathology, Adelaide, South Australia 5000, Australia;

    Department of Biochemistry, La Trobe University, Bundoora, Victoria 3083, Australia;

    Department of Obstetrics and Gynecology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;

    Department of Anatomy and Histology, University of Sydney, New South Wales 2006, Australia;

    Department of Biochemistry, La Trobe University, Bundoora, Victoria 3083, Australia;

    Center for Cancer Biology, SA Pathology, Adelaide, South Australia 5000, Australia;

    Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cobalt; iron; Nedd4-2; ubiquitin;

    机译:钴;铁;Nedd4-2;泛素;

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