Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression.
Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression.
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DOI：
10.1523/jneurosci.6577-10.2011
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发表时间：
2011-05-18
期刊：
影响因子：
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通讯作者：
Swanson RA
中科院分区：
文献类型：
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作者：
Escartin C;Won SJ;Malgorn C;Auregan G;Berman AE;Chen PC;Déglon N;Johnson JA;Suh SW;Swanson RA
星形胶质细胞通过释放谷胱甘肽来支持神经元的抗氧化能力，谷胱甘肽在脑细胞外空间中裂解为半胱氨酸。然后，神经元通过兴奋性氨基酸转运蛋白3 [EAAT 3;也称为Slc 1a 1（溶质载体家族1成员1）]摄取游离半胱氨酸，以支持谷胱甘肽的从头合成。核因子红细胞2相关因子2（Nrf 2）-抗氧化反应元件（ARE）途径的激活通过氧化应激促进星形胶质细胞释放谷胱甘肽，但它仍然是未知的，这种释放是如何耦合到神经元谷胱甘肽的合成。在这里，我们评估了神经元半胱氨酸转运蛋白EAAT 3的转录调控Nrf 2-ARE途径。在C6细胞中，Nrf 2激活剂和Nrf 2过表达均产生EAAT 3转录激活。在几种哺乳动物的EAAT 3启动子中发现了保守的ARE相关序列。通过染色质免疫沉淀法观察到，这种ARE相关序列在体内小鼠神经元中被Nrf 2结合。小鼠脑中Nrf 2-ARE通路的化学激活增加了神经元EAAT 3水平和神经元谷胱甘肽含量，并且这些作用在Nrf 2或EAAT 3遗传缺陷的小鼠中被消除。通过慢病毒基因转移在脑神经元中选择性过表达Nrf 2足以上调神经元EAAT 3蛋白和谷胱甘肽含量。这些发现确定了一种机制，即Nrf 2激活可以协调星形胶质细胞谷胱甘肽释放与神经元谷胱甘肽合成通过转录上调神经元EAAT 3表达。
Astrocytes support neuronal antioxidant capacity by releasing glutathione, which is cleaved to cysteine in brain extracellular space. Free cysteine is then taken up by neurons through excitatory amino acid transporter 3 [EAAT3; also termed Slc1a1 (solute carrier family 1 member 1)] to support de novo glutathione synthesis. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) pathway by oxidative stress promotes astrocyte release of glutathione, but it remains unknown how this release is coupled to neuronal glutathione synthesis. Here we evaluated transcriptional regulation of the neuronal cysteine transporter EAAT3 by the Nrf2-ARE pathway. Nrf2 activators and Nrf2 overexpression both produced EAAT3 transcriptional activation in C6 cells. A conserved ARE-related sequence was found in the EAAT3 promoter of several mammalian species. This ARE-related sequence was bound by Nrf2 in mouse neurons in vivo as observed by chromatin immunoprecipitation. Chemical activation of the Nrf2-ARE pathway in mouse brain increased both neuronal EAAT3 levels and neuronal glutathione content, and these effects were abrogated in mice genetically deficient in either Nrf2 or EAAT3. Selective overexpression of Nrf2 in brain neurons by lentiviral gene transfer was sufficient to upregulate both neuronal EAAT3 protein and glutathione content. These findings identify a mechanism whereby Nrf2 activation can coordinate astrocyte glutathione release with neuronal glutathione synthesis through transcriptional upregulation of neuronal EAAT3 expression.