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首页> 外文期刊>Biotechnology Advances: An International Review Journal >Monitoring Keap1-Nrf2 interactions in single live cells
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Monitoring Keap1-Nrf2 interactions in single live cells

机译：监控单个活细胞中的Keap1-Nrf2相互作用

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The transcription factor NF-E2 p45-related factor 2 (Nrf2) and its negative regulator Kelch-like ECH associated protein 1 (Keap1) control the expression of nearly 500 genes with diverse cytoprotective functions. Keap1, a substrate adaptor protein for Cullin3/Rbx1 ubiquitin ligase, normally continuously targets Nrf2 for degradation, but loses this ability in response to electrophiles and oxidants (termed inducers). Consequently, Nrf2 accumulates and activates transcription of its downstream target genes. Many inducers are phytochemicals, and cruciferous vegetables represent one of the richest sources of inducer activity among the most commonly used edible plants. Here we summarize the discovery of the isothiocyanate sulforaphane as a potent inducer which reacts with cysteine sensors of Keap1, leading to activation of Nrf2. We then describe the development of a quantitative Forster resonance energy transfer (FRET)-based methodology combined with multiphoton fluorescence lifetime imaging microscopy (FLIM) to investigate the interactions between Keap1 and Nrf2 in single live cells, and the effect of sulforaphane, and other cysteine-reactive inducers, on the dynamics of the Keap1-Nrf2 protein complex. We present the experimental evidence for the "cyclic sequential attachment and regeneration" or "conformation cycling" model of Keap1-mediated Nrf2 degradation. Finally, we discuss the implications of this mode of regulation of Nrf2 for achieving a fine balance under normal physiological conditions, and the consequences and mechanisms of disrupting this balance for tumor biology
机译：转录因子NF-E2 p45相关因子2（Nrf2）及其负调控因子Kelch样ECH相关蛋白1（Keap1）控制着近500种具有多种细胞保护功能的基因的表达。 Keap1是Cullin3 / Rbx1泛素连接酶的底物衔接子蛋白，通常连续靶向Nrf2进行降解，但由于亲电子试剂和氧化剂（称为诱导剂）而失去这种能力。因此，Nrf2积累并激活其下游靶基因的转录。许多诱导剂是植物化学物质，十字花科蔬菜是最常用的食用植物中诱导剂活性最丰富的来源之一。在这里，我们总结了异硫氰酸酯萝卜硫素作为有效诱导剂的发现，该诱导剂与Keap1的半胱氨酸传感器反应，导致Nrf2激活。然后，我们描述了基于定量Forster共振能量转移（FRET）的方法与多光子荧光寿命成像显微镜（FLIM）的结合，以研究Keap1和Nrf2在单个活细胞中的相互作用以及萝卜硫烷和其他半胱氨酸的影响-反应性诱导物，涉及Keap1-Nrf2蛋白复合物的动力学。我们提出了Keap1介导的Nrf2降解的“循环顺序附着和再生”或“构象循环”模型的实验证据。最后，我们讨论了这种Nrf2调节模式对于在正常生理条件下实现精细平衡的意义，以及破坏这种平衡对肿瘤生物学的影响和机制。

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