Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease.
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DOI：
10.1016/j.freeradbiomed.2015.06.021
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发表时间：
2015-11
影响因子：
7.4
通讯作者：
Hayes JD
中科院分区：
文献类型：
--
作者：
Tebay LE;Robertson H;Durant ST;Vitale SR;Penning TM;Dinkova-Kostova AT;Hayes JD
核因子-红细胞2 p45相关因子2（Nrf 2）调节一系列基因的基础和应激诱导表达，这些基因编码基于谷胱甘肽和硫氧还蛋白的抗氧化系统的关键组分，以及醛酮还原酶、谷胱甘肽S-转移酶和NAD（P）H：醌氧化还原酶-1药物代谢同工酶沿着多药耐药相关外排泵。因此，它在对活性氧（ROS）和外源性物质的内在抗性和细胞适应中起着关键作用。然而，Nrf 2的激活可以作为一把双刃剑，因为它诱导的一些基因可能通过促进多环芳烃代谢物的无效氧化还原循环而导致化学致癌，或者通过增加外排泵的表达而赋予对化疗药物的抗性，这表明其细胞保护作用将以特定的方式变化。除了细胞保护，Nrf 2还控制参与中间代谢的基因，积极调节参与NADPH生成、嘌呤生物合成和脂肪酸β-氧化的基因，同时抑制参与脂肪生成和脂肪生成的基因。nrf 2受到多个级别的监管。它协调适应氧化剂和亲电子物质的能力主要是由于其抑制子之一Kelch样ECH相关蛋白1（Keap 1）内的硫醇的应激刺激修饰，该蛋白存在于cullin-3 RING遍在蛋白连接酶（CRL）中。复合物CRLKeap 1。因此，Keap 1中Cys残基的修饰阻断了CRLKeap 1的活性，使新翻译的Nrf 2快速积累并诱导其靶基因。Keap 1抑制Nrf 2的能力可以通过p62/多价螯合体-1以雷帕霉素复合物1（mTORC 1）依赖的机制靶点的方式减弱，从而允许禁食后再进食以增加Nrf 2靶基因表达。与Keap 1的阻遏平行，Nrf 2也被Skp 1-cullin-1-F-box蛋白（SCF）泛素连接酶复合物SCFβ-TrCP中的β-transducin repeat-containing protein（β-TrCP）阻遏。SCFβ-TrCP抑制Nrf 2活性的能力本身通过糖原合成酶激酶-3（GSK-3）通过形成含DSGIS的磷酸降解决定子而预先磷酸化转录因子而增强。然而，通过GSK-3在Nrf 2中形成磷酸降解决定子被激活蛋白激酶B（PKB）/Akt的刺激物抑制。特别是，PKB/Akt活性可以通过磷酸肌醇3-激酶和mTORC 2增加，从而提供了为什么抗氧化剂响应元件驱动的基因是由生长因子和营养素诱导的解释。因此，Nrf 2活性通过氧化应激和基于能量的信号通过CRLKeap 1和SCFβ-TrCP严格控制，使其能够介导恢复氧化还原稳态和调节中间代谢的适应性反应。基于Nrf 2以积极和消极的方式影响多种生化途径的事实，就对某些退行性疾病的易感性而言，其剂量反应曲线可能是U形的。具体而言，太少的Nrf 2活性将导致细胞保护的丧失、抗氧化能力的降低和脂肪酸的β-氧化的降低，同时相反地还表现出对涉及受体酪氨酸激酶和凋亡信号调节激酶-1的ROS基信号传导的敏感性的提高。相比之下，过多的Nrf 2活性扰乱了有利于还原的稳态平衡，因此可能具有有害的后果，包括还原型谷胱甘肽和NADPH的过度产生、基于ROS的信号转导的钝化、上皮细胞增生和某些细胞类型不能正确分化。我们讨论了一个假定的U形Nrf 2剂量反应曲线的基础上潜在的竞争过程相关的不同阶段的肿瘤发生。
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and stress-inducible expression of a battery of genes encoding key components of the glutathione-based and thioredoxin-based anti-oxidant systems, as well as aldo-keto reductase, glutathione S-transferase, and NAD(P)H:quinone oxi-doreductase-1 drug-metabolizing isoenzymes along with multidrug-resistance-associated efflux pumps. It therefore plays a pivotal role in both intrinsic resistance and cellular adaptation to reactive oxygen species (ROS) and xenobiotics. Activation of Nrf2 can, however, serve as a double-edged sword because some of the genes it induces may contribute to chemical carcinogenesis by promoting futile redox cycling of polycyclic aromatic hydrocarbon metabolites or confer resistance to chemotherapeutic drugs by increasing the expression of efflux pumps, suggesting its cytoprotective effects will vary in a context-specific fashion. In addition to cytoprotection, Nrf2 also controls genes involved in intermediary metabolism, positively regulating those involved in NADPH generation, purine biosynthesis, and the β-oxidation of fatty acids, while suppressing those involved in lipogenesis and gluconeogenesis. Nrf2 is subject to regulation at multiple levels. Its ability to orchestrate adaptation to oxidants and electrophiles is due principally to stress-stimulated modification of thiols within one of its repressors, the Kelch-like ECH-associated protein 1 (Keap1), which is present in the cullin-3 RING ubiquitin ligase (CRL) complex CRLKeap1. Thus modification of Cys residues in Keap1 blocks CRLKeap1 activity, allowing newly translated Nrf2 to accumulate rapidly and induce its target genes. The ability of Keap1 to repress Nrf2 can be attenuated by p62/sequestosome-1 in a mechanistic target of rapamycin complex 1 (mTORC1)-depen-dent manner, thereby allowing refeeding after fasting to increase Nrf2-target gene expression. In parallel with repression by Keap1, Nrf2 is also repressed by β-transducin repeat-containing protein (β-TrCP), present in the Skp1–cullin-1–F-box protein (SCF) ubiquitin ligase complex SCFβ-TrCP. The ability of SCFβ-TrCP to suppress Nrf2 activity is itself enhanced by prior phosphorylation of the transcription factor by glycogen synthase kinase-3 (GSK-3) through formation of a DSGIS-containing phosphodegron. However, formation of the phosphodegron in Nrf2 by GSK-3 is inhibited by stimuli that activate protein kinase B (PKB)/Akt. In particular, PKB/Akt activity can be increased by phosphoinositide 3-kinase and mTORC2, thereby providing an explanation of why antioxidant-responsive element-driven genes are induced by growth factors and nutrients. Thus Nrf2 activity is tightly controlled via CRLKeap1 and SCFβ-TrCP by oxidative stress and energy-based signals, allowing it to mediate adaptive responses that restore redox homeostasis and modulate intermediary metabolism. Based on the fact that Nrf2 influences multiple biochemical pathways in both positive and negative ways, it is likely its dose–response curve, in terms of susceptibility to certain degenerative disease, is U-shaped. Specifically, too little Nrf2 activity will lead to loss of cytoprotection, diminished antioxidant capacity, and lowered β-oxidation of fatty acids, while conversely also exhibiting heightened sensitivity to ROS-based signaling that involves receptor tyrosine kinases and apoptosis signal-regulating kinase-1. By contrast, too much Nrf2 activity disturbs the homeostatic balance in favor of reduction, and so may have deleterious consequences including overproduction of reduced glutathione and NADPH, the blunting of ROS-based signal transduction, epithelial cell hyperplasia, and failure of certain cell types to differentiate correctly. We discuss the basis of a putative U-shaped Nrf2 dose–response curve in terms of potentially competing processes relevant to different stages of tumorigenesis.