Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2
Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2
复制标题
DOI：
10.1128/mcb.00630-07
复制
发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Zhang, Donna D.
中科院分区：
文献类型：
--
作者：
Sun, Zheng;Zhang, Shirley;Zhang, Donna D.
转录因子 Nrf2 调节细胞氧化还原稳态。在基础条件下，Keap1 将 Nrf2 招募到含有 Cul3 的 E3 泛素连接酶复合物中，以进行泛素缀合和随后的蛋白酶体降解。氧化应激通过抑制 E3 泛素连接酶活性触发 Nrf2 激活，导致 Nrf2 水平升高和 Nrf2 依赖性基因转录激活。在本研究中，我们将 Keap1 确定为 Nrf2 的关键诱导后阻遏蛋白，并证明 Keap1 中的核输出序列 (NES) 是通过护送 Nrf2 核输出来终止 Nrf2 抗氧化反应元件 (ARE) 信号传导所必需的。我们提供的证据表明 Nrf2 泛素化是在细胞质中进行的。此外，我们表明 Keap1 核易位不依赖于 Nrf2，并且 Nrf2-Keap1 复合物不结合 ARE。总的来说，我们的结果表明了以下诱导后抑制机制：在细胞氧化还原稳态恢复后，Keapl 易位到细胞核中，使 Nrf2 从 ARE 上解离。 Nrf2-Keap1 复合物随后由 Keapl 中的 NES 转运出细胞核。一旦进入细胞质，Keap1-Nrf2 复合物就会与 E3 泛素连接酶结合，导致 Nrf2 降解并终止 Nrf2 信号通路。因此，Nrf2介导的抗氧化反应的诱导后抑制是由Keapl的核输出功能与细胞质泛素化和降解机制联合控制的。
The transcription factor Nrf2 regulates cellular redox homeostasis. Under basal conditions, Keap1 recruits Nrf2 into the Cul3-containing E3 ubiquitin ligase complex for ubiquitin conjugation and subsequent proteasomal degradation. Oxidative stress triggers activation of Nrf2 through inhibition of E3 ubiquitin ligase activity, resulting in increased levels of Nrf2 and transcriptional activation of Nrf2-dependent genes. In this study, we identify Keap1 as a key postinduction repressor of Nrf2 and demonstrate that a nuclear export sequence (NES) in Keap1 is required for termination of Nrf2-antioxidant response element (ARE) signaling by escorting nuclear export of Nrf2. We provide evidence that ubiquitination of Nrf2 is carried out in the cytosol. Furthermore, we show that Keapl nuclear translocation is independent of Nrf2 and the Nrf2-Keap1 complex does not bind the ARE. Collectively, our results suggest the following mechanism of postinduction repression: upon recovery of cellular redox homeostasis, Keapl translocates into the nucleus to dissociate Nrf2 from the ARE. The Nrf2-Keap1 complex is then transported out of the nucleus by the NES in Keapl. Once in the cytoplasm, the Keap1-Nrf2 complex associates with the E3 ubiquitin ligase, resulting in degradation of Nrf2 and termination of the Nrf2 signaling pathway. Hence, postinduction repression of the Nrf2-mediated antioxidant response is controlled by the nuclear export function of Keapl in alliance with the cytoplasmic ubiquitination and degradation machinery.