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首页> 外文期刊>Molecular and Cellular Biology >KPNA6 (Importin α7)-Mediated Nuclear Import of Keap1 Represses the Nrf2-Dependent Antioxidant Response
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KPNA6 (Importin α7)-Mediated Nuclear Import of Keap1 Represses the Nrf2-Dependent Antioxidant Response

机译：KPNA6（进口α7）介导的Keap1核进口抑制Nrf2依赖的抗氧化反应。

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The transcription factor Nrf2 has emerged as a master regulator of cellular redox homeostasis. As an adaptive response to oxidative stress, Nrf2 activates the transcription of a battery of genes encoding antioxidants, detoxification enzymes, and xenobiotic transporters by binding the cis-antioxidant response element in the promoter regions of genes. The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1, which targets Nrf2 for redox-sensitive ubiquitin-mediated degradation in the cytoplasm and exports Nrf2 from the nucleus. However, it is not clear how Keap1 gains access to the nucleus. In this study, we show that Keap1 is constantly shuttling between the nucleus and the cytoplasm under physiological conditions. The nuclear import of Keap1 requires its C-terminal Kelch domain and is independent of Nrf1 and Nrf2. We have determined that importin α7, also known as karyopherin α6 (KPNA6), directly interacts with the Kelch domain of Keap1. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows down Keap1 nuclear import and enhances the Nrf2-mediated adaptive response induced by oxidative stress. Furthermore, KPNA6 accelerates the clearance of Nrf2 protein from the nucleus during the postinduction phase, therefore promoting restoration of the Nrf2 protein to basal levels. These findings demonstrate that KPNA6-mediated Keap1 nuclear import plays an essential role in modulating the Nrf2-dependent antioxidant response and maintaining cellular redox homeostasis.
机译：转录因子Nrf2已成为细胞氧化还原稳态的主要调节剂。作为对氧化应激的适应性反应，Nrf2通过在基因启动子区域结合顺式抗氧化反应元件来激活一系列编码抗氧化剂，解毒酶和异种生物转运蛋白的基因的转录。可诱导的Nrf2信号传导的强度和持续时间由Keap1精细地控制在多个水平上，Keap1将Nrf2靶向氧化还原敏感的泛素介导的细胞质降解并从细胞核中输出Nrf2。但是，尚不清楚Keap1如何获得对核的访问。在这项研究中，我们表明Keap1在生理条件下不断穿梭在细胞核和细胞质之间。 Keap1的核输入需要其C端Kelch域，并且独立于Nrf1和Nrf2。我们已经确定importinα7，也称为核转运蛋白α6（KPNA6），直接与Keap1的Kelch域相互作用。 KPNA6的过表达促进了Keap1核的导入并减弱了Nrf2信号传导，而敲低KPNA6则减缓了Keap1的核导入并增强了氧化应激诱导的Nrf2介导的适应性反应。此外，在诱导后阶段，KPNA6加速了Nrf2蛋白从细胞核的清除，因此促进了Nrf2蛋白的恢复至基础水平。这些发现表明，KPNA6介导的Keap1核导入在调节依赖Nrf2的抗氧化反应和维持细胞氧化还原稳态方面起着至关重要的作用。

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