Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
Oxid Med Cell Longev. 2023 Jan 10;2023:4743885. doi: 10.1155/2023/4743885. eCollection 2023.
Increased accumulation of reactive oxygen species (ROS) and decline of adaptive response of antioxidants to oxidative stimuli has been implicated in the aging process. Nuclear factor erythroid 2-related factor 2 (Nrf2) activation is a core event in attenuating oxidative stress-associated aging. The activity is modulated by a more complex regulatory network. In this study, we demonstrate the proteasome activator REG function as a new regulator of Nrf2 activity upon oxidative stress in cell aging model induced by hydrogen peroxide (HO). REG deficiency promotes cell senescence in primary MEF cells after HO treatment. Accordingly, ROS scavenging is accelerated in WT cells but blunted in REG lacking cells during 12-hour recovery from a 1-hour HO treatment, indicating long-lasting antioxidant buffering capacity of REG. Mechanistically, through GSK-3 inhibition, REG enhances the nuclear distribution and transcriptional activity of Nrf2, which is surveyed by induction of phase II enzymes including Ho1 and Nqo1. Meanwhile, Nrf2 mediates the transcriptional activation of REG upon HO stimulation. More interestingly, short-term exposure to HO leads to transiently upregulation and gradually descent of REG transcription, however sustained higher REG protein level even in the absence of HO for 24 hours. Thus, our results establish a positive feedback loop between REG and Nrf2 and a new layer of adaptive response after oxidative stimulation that is the REG-GSK-3-Nrf2 pathway.
活性氧（ROS）的积累增加和抗氧化剂对氧化刺激的适应性反应下降与衰老过程有关。核因子红细胞 2 相关因子 2（Nrf2）的激活是减轻与氧化应激相关的衰老的核心事件。其活性受更复杂的调控网络调节。在这项研究中，我们证明蛋白酶体激活剂 REG 在过氧化氢（HO）诱导的细胞衰老模型中作为 Nrf2 活性的新调节剂。在 HO 处理后，REG 缺乏会促进原代 MEF 细胞的衰老。因此，在从 1 小时 HO 处理中恢复 12 小时期间，WT 细胞中的 ROS 清除加速，但在缺乏 REG 的细胞中减弱，表明 REG 具有持久的抗氧化缓冲能力。在机制上，通过抑制 GSK-3，REG 增强了 Nrf2 的核分布和转录活性，这可以通过诱导包括 Ho1 和 Nqo1 在内的 II 期酶来检测。同时，Nrf2 介导 HO 刺激后 REG 的转录激活。更有趣的是，短期暴露于 HO 会导致 REG 转录的瞬时上调和逐渐下降，但即使在没有 HO 的情况下持续 24 小时，REG 蛋白水平仍保持较高水平。因此，我们的结果在氧化刺激后建立了 REG 和 Nrf2 之间的正反馈回路以及适应性反应的新层次，即 REG-GSK-3-Nrf2 途径。
