Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response.
Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response.
复制标题
DOI：
10.1089/ars.2014.5962
复制
发表时间：
2015-09-01
影响因子：
6.6
通讯作者：
Thornalley PJ
中科院分区：
文献类型：
--
作者：
Xue M;Momiji H;Rabbani N;Barker G;Bretschneider T;Shmygol A;Rand DA;Thornalley PJ
目的：由核因子红细胞2相关因子2（Nrf 2）协调的应激应答信号传导提供了保护细胞免受毒性损伤、氧化应激和代谢功能障碍的适应性应答。Nrf 2通过与调节性抗氧化反应元件（战神）结合来调节一系列保护性基因。本研究的目的是研究Nrf 2如何信号细胞应激状态和调节转录，以维持稳态。结果如下：在活细胞显微镜下，我们观察到Nrf 2在细胞质和细胞核之间进行自主易位频率调制振荡。振荡发生在静止期，当细胞在生理水平的激活剂刺激时，它们的周期和幅度减小，然后引起细胞保护性转录反应。我们提出了一种机制，即振荡产生的负反馈，涉及连续的去磷酸化和磷酸化步骤。Nrf 2在细胞核中失活，并在返回细胞质后重新激活。在应激条件下，Nrf 2返回细胞质的频率增加，再激活或刷新率增加，激活了介导细胞保护作用的转录反应。丝氨酸/苏氨酸蛋白磷酸酶PGAM 5，Nrf 2相互作用组的成员，是一个关键的调节成分。创新：我们发现Nrf 2在细胞中被激活，而总细胞Nrf 2蛋白浓度没有变化。ARE连锁的保护性基因转录的调节通过Nrf 2的易位振荡而发生。我们发现Nrf 2的细胞质刷新率在维持和调节转录反应中是重要的，并且将应激挑战与增加的细胞质监视联系起来。我们发现PGAM 5的沉默和抑制提供了Nrf 2的有效激活。结论：Nrf 2的频率调控易位振荡介导ARE连锁的细胞保护性转录反应。抗氧化剂。氧化还原信号。23，613-629。
Aims: Stress responsive signaling coordinated by nuclear factor erythroid 2-related factor 2 (Nrf2) provides an adaptive response for protection of cells against toxic insults, oxidative stress and metabolic dysfunction. Nrf2 regulates a battery of protective genes by binding to regulatory antioxidant response elements (AREs). The aim of this study was to examine how Nrf2 signals cell stress status and regulates transcription to maintain homeostasis. Results: In live cell microscopy we observed that Nrf2 undergoes autonomous translocational frequency-modulated oscillations between cytoplasm and nucleus. Oscillations occurred in quiescence and when cells were stimulated at physiological levels of activators, they decrease in period and amplitude and then evoke a cytoprotective transcriptional response. We propose a mechanism whereby oscillations are produced by negative feedback involving successive de-phosphorylation and phosphorylation steps. Nrf2 was inactivated in the nucleus and reactivated on return to the cytoplasm. Increased frequency of Nrf2 on return to the cytoplasm with increased reactivation or refresh-rate under stress conditions activated the transcriptional response mediating cytoprotective effects. The serine/threonine-protein phosphatase PGAM5, member of the Nrf2 interactome, was a key regulatory component. Innovation: We found that Nrf2 is activated in cells without change in total cellular Nrf2 protein concentration. Regulation of ARE-linked protective gene transcription occurs rather through translocational oscillations of Nrf2. We discovered cytoplasmic refresh rate of Nrf2 is important in maintaining and regulating the transcriptional response and links stress challenge to increased cytoplasmic surveillance. We found silencing and inhibition of PGAM5 provides potent activation of Nrf2. Conclusion: Frequency modulated translocational oscillations of Nrf2 mediate the ARE-linked cytoprotective transcriptional response. Antioxid. Redox Signal. 23, 613–629.