翻译后修饰对转录因子NF-E2相关因子2功能的调控

Regulation of NRF2 by Post-translational Modifications

抗氧化反应组件(AREs)普遍存在于编码抗氧化和/或解毒酶基因的启动子区域,为这些基因的转录启动所必需;而这些基因的表达对维持细胞内氧化还原稳态,抵抗活性氧类(ROS)引起的细胞损伤发挥重要作用。转录因子NF-E2相关因子2(nuclear factor erythroid-2 related factor 2,NRF2)作为抗氧化反应中的关键转录因子,可以与ARE结合,启动其下游靶基因,在氧化应激及亲电子剂应激中发挥重要的调控作用,广泛参与炎症、增殖、凋亡、细胞分化、组织再生和代谢等过程;因此,激活NRF2有望成为治疗肿瘤及其他与氧化、炎症相关疾病的新策略。蛋白质的翻译后修饰,对蛋白质空间构象、稳定性及其与其他蛋白质间相互作用具有重要作用。因此,探究NRF2的翻译后修饰如磷酸化、乙酰化和泛素化的修饰过程等,对深入了解NRF2的功能及调控机制至关重要,并与某些疾病的发生发展密切相关。本文对近年来翻译后修饰对NRF2的活性及功能的调控进行综述。

Antioxidant responsive elements （AREs） are common in the promoter region of genes coding antioxidant and/or detoxifying enzymes. AREs are essential to activate these genes, whose expression is crucial to maintain the homeostasis of intracellular redox levels and protect cells against reactive oxygen species （ROS）-induced lesions. The nuclear factor erythroid-2 related factor 2 （NRF2）, a critical transcription factor responsible for transcriptional activation of ARE-dependent genes, plays an important role in oxidative stress and electrophilic reagent stress and is involved in a variety of cellular processes including inflammation, cellular proliferation and differentiation, apoptosis, tissue regeneration and metabolism. Therefore, activating NRF2 could be a novel tactics for cancer therapy as well as diseases associated with oxidation or inflammation. The post-translational modifications （PTMs） of proteins mediate conformation alteration, stability and the interaction with other proteins. Consequently, PTMs of NRF2 such as phosphorylation, acetylation and ubiquitination are critical to its function, and thus closely related to certain disease development and progression. Here we review the mechanistic studies of NRF2 PTMs in recent years.