The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds
The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds
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DOI：
10.1128/mcb.01080-08
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发表时间：
2009-01-15
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
动物已经进化出防御系统，以便在化学多样化的环境中生存。此类系统应表现出可塑性，例如适应性免疫，甚至能够对未知化学物质做出反应。抗氧化转录因子 Nrf2 会响应各种亲电子试剂而被激活，并诱导细胞保护酶对其进行解毒。我们在此报告利用斑马鱼和 11 种 Nrf2 激活化合物发现了 Nrf2 激活的多重传感机制。首先，我们表明，测试的六种化合物专门针对 Keap1（Nrf2 的泛素连接酶）中的 Cys-151，而两种化合物则针对 Cys-273。其次，除了 Nrf2 和 Keap1 之外，第三个因素被认为是对其中三种化合物做出反应所必需的。最后，我们分离出一种斑马鱼突变体，它对七种化合物的反应有缺陷，但对其余四种化合物没有反应。这些结果使我们将 Nrf2 激活剂分为六类，并假设多重传感可以增强系统的可塑性。
Animals have evolved defense systems for surviving in a chemically diverse environment. Such systems should demonstrate plasticity, such as adaptive immunity, enabling a response to even unknown chemicals. The antioxidant transcription factor Nrf2 is activated in response to various electrophiles and induces cytoprotective enzymes that detoxify them. We report here the discovery of a multiple sensing mechanism for Nrf2 activation using zebrafish and 11 Nrf2-activating compounds. First, we showed that six of the compounds tested specifically target Cys-151 in Keap1, the ubiquitin ligase for Nrf2, while two compounds target Cys-273. Second, in addition to Nrf2 and Keap1, a third factor was deemed necessary for responding to three of the compounds. Finally, we isolated a zebrafish mutant defective in its response to seven compounds but not in response to the remaining four. These results led us to categorize Nrf2 activators into six classes and hypothesize that multiple sensing allows enhanced plasticity in the system.