Wufuer Reziyamu, Fan Zhuo, Liu Keli, Zhang Yiguo
Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing 400044, China.
Antioxidants (Basel). 2021 Oct 13;10(10):1610. doi: 10.3390/antiox10101610.
In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)-rather than Nrf2-is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., , , and ) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to -butylhydroquinone (BHQ) serving as a pro-oxidative stressor. In cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α's function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of BHQ, against apoptotic damages. By contrast, cells gave rise to a substantial reduction of Nrf1 in both basal and BHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of expression resulted from the constitutive active cells, which were not manifested with oxidative stress, whether or not it was intervened with BHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or BHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2's functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.
在过去25年里，Nrf2（核因子红细胞2相关因子2，也称为NFE2L2）一直被优先视为调节抗氧化、解毒和细胞保护基因的主要枢纽；然而事实上，在正常生长和发育过程中，对于细胞内稳态和器官完整性而言，Nrf1（核因子红细胞2相关因子1，也称为NFE2L1）而非Nrf2是不可或缺的。在此，利用不同基因型的细胞系（即 、 和 ）来确定Nrf1和Nrf2在介导抗氧化反应基因对作为促氧化应激源的叔丁基对苯二酚（BHQ）的反应中所起的不同但又相互关联的作用。在 细胞中，Nrf2高度积累，但在其针对内源性氧化应激的基础细胞保护反应中，仍无法完全补偿Nrf1α功能的特定缺失，尽管它在对凋亡损伤的抗氧化反应（如BHQ的兴奋效应）中发挥了部分诱导作用。相比之下， 细胞在基础和BHQ刺激的表达水平上Nrf1均大幅降低，从而导致明显的氧化应激，但它仍能介导有效的抗氧化反应，并伴随着氧化型谷胱甘肽（GSSG）与还原型谷胱甘肽（GSH）的比例显著降低。相反，组成型活性 的细胞中 表达显著增加，无论是否用BHQ干预，均未表现出氧化应激。进一步研究了Nrf1和Nrf2对抗氧化和解毒基因（编码HO-1、NQO1、GCLC、GCLM、GSR、GPX1、TALDO、MT1E和MT2）以及超氧化物歧化酶（SOD）和过氧化氢酶（CAT）清除活性氧（ROS）的相互调节作用。综合结果表明，在相互调节网络中，Nrf1和Nrf2对精细调节抗氧化细胞保护基因基础组成型和/或BHQ诱导型表达水平做出了独特而协同的贡献。总体而言Nrf1对Nrf2的功能起到制动控制作用，使其局限在一定范围内，而其转录则受Nrf2调节
