DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway
DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway
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DOI：
10.1093/hmg/dds131
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发表时间：
2012-07-01
影响因子：
3.5
通讯作者：
Mouradian, M. Maral
中科院分区：
文献类型：
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作者：
Im, Joo-Young;Lee, Kang-Woo;Mouradian, M. Maral
DJ-1 突变时与隐性遗传性帕金森病有关，是一种具有抗氧化和转录调节活性的多功能蛋白质。然而，DJ-1 及其调节的基因提供神经保护的机制尚不完全清楚。在这里，我们发现野生型 DJ-1 诱导硫氧还蛋白 1 (Trx1)（一种蛋白质二硫键氧化还原酶）的表达，而致病性突变亚型 L166P 和 M26I 则不能。相反，SH-SY5Y 细胞中的 DJ-1 敲低和小鼠中的 DJ-1 敲除会导致 Trx1 蛋白和 mRNA 表达水平显着降低。使用 Trx 还原酶药理学抑制剂、1-氯-2,4-二硝基苯和 Trx1 siRNA 证实了 Trx1 在 DJ-1 细胞保护功能中的重要性。这两种方法都会导致 DJ-1 介导的保护作用部分丧失。此外，Trx1 的敲低可显着消除 DJ-1 依赖性、过氧化氢诱导的促生存因子 AKT 的激活。对人类 Trx1 基因的启动子分析发现了一个抗氧化反应元件 (ARE)，它是 DJ-1 依赖性诱导 Trx1 表达所必需的。转录因子核因子 erythroid-2 相关因子 2 (Nrf2) 是 ARE 介导表达的关键诱导剂，受 DJ-1 调节。 DJ-1 的过度表达导致 Nrf2 蛋白水平增加，促进其易位到细胞核中，并增强其招募到 Trx1 启动子中的 ARE 位点上。此外，Nrf2 敲低消除了 DJ-1 介导的 Trx1 诱导和针对过氧化氢的细胞保护，表明 Nrf2 在执行 DJ-1 对抗氧化应激的保护功能中发挥着关键作用。这些发现提供了一种新机制，通过 Nrf2 介导的转录诱导增加 Trx1 表达，从而支持 DJ-1 的抗氧化功能。
DJ-1, which is linked to recessively inherited Parkinsons disease when mutated, is a multi-functional protein with anti-oxidant and transcription regulatory activities. However, the mechanism(s) through which DJ-1 and the genes it regulates provide neuroprotection is not fully understood. Here, we show that wild-type DJ-1 induces the expression of thioredoxin 1 (Trx1), a protein disulfide oxidoreductase, whereas pathogenic mutant isoforms L166P and M26I cannot. Conversely, DJ-1 knockdown in SH-SY5Y cells and DJ-1 knockout in mice result in significant decrease in Trx1 protein and mRNA expression levels. The importance of Trx1 in the cytoprotective function of DJ-1 is confirmed using a pharmacological inhibitor of Trx reductase, 1-chloro-2,4-dinitrobenzene, and Trx1 siRNA. Both approaches result in partial loss of DJ-1-mediated protection. Additionally, knockdown of Trx1 significantly abrogates DJ-1-dependent, hydrogen peroxide-induced activation of the pro-survival factor AKT. Promoter analysis of the human Trx1 gene identified an antioxidant response element (ARE) that is required for DJ-1-dependent induction of Trx1 expression. The transcription factor Nuclear factor erythroid-2 related factor 2 (Nrf2), which is a critical inducer of ARE-mediated expression, is regulated by DJ-1. Overexpression of DJ-1 results in increased Nrf2 protein levels, promotes its translocation into the nucleus and enhances its recruitment onto the ARE site in the Trx1 promoter. Further, Nrf2 knockdown abolishes DJ-1-mediated Trx1 induction and cytoprotection against hydrogen peroxide, indicating the critical role of Nrf2 in carrying out the protective functions of DJ-1 against oxidative stress. These findings provide a new mechanism to support the antioxidant function of DJ-1 by increasing Trx1 expression via Nrf2-mediated transcriptional induction.