Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
Biochemistry (Mosc). 2021 Apr;86(4):433-448. doi: 10.1134/S0006297921040052.
This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback loops. The Nrf2 pathway is believed to be a component of the anti-aging program responsible for the healthspan and longevity. Nrf2 enables stress adaptation by activating cell antioxidant defense and other metabolic processes via control of expression of over 200 target genes in response to various types of stress. The GSK3 system represents a "regulating valve" that controls fine oscillations in the Nrf2 level, unlike Keap1, which prevents significant changes in the Nrf2 content in the absence of oxidative stress and which is inactivated by the oxidative stress. Furthermore, GSK3 modifies core circadian clock proteins (Bmal1, Clock, Per, Cry, and Rev-erbα). Phosphorylation by GSK3 leads to the inactivation and degradation of circadian rhythm-activating proteins (Bmal1 and Clock) and vice versa to the activation and nuclear translocation of proteins suppressing circadian rhythms (Per and Rev-erbα) with the exception of Cry protein, which is likely to be implicated in the fine tuning of biological clock. Functionally, GSK3 appears to be one of the hubs in the cross-regulation of circadian rhythms and antioxidant defense. Here, we present the data on the crosstalk between the most powerful cell antioxidant mechanism, the Nrf2 system, and the biorhythm-regulating system in mammals, including the impact of GSK3 overexpression and knockout on the Nrf2 signaling. Understanding the interactions between the regulatory cascades linking homeostasis maintenance and cell response to oxidative stress will help in elucidating molecular mechanisms that underlie aging and longevity.
本文讨论了将昼夜节律与代谢联系起来的遗传和分子途径，从而产生了正、负调节反馈环。Nrf2 途径被认为是抗衰老程序的一个组成部分，负责健康寿命和长寿。Nrf2 通过激活细胞抗氧化防御和其他代谢过程，在各种类型的应激下，通过控制超过 200 个靶基因的表达，使细胞适应应激。GSK3 系统代表了一种“调节阀”，通过控制 Nrf2 水平的精细波动来控制 Nrf2 水平，而不同于 Keap1，Keap1 在没有氧化应激的情况下阻止 Nrf2 含量的显著变化，并在氧化应激下失活。此外，GSK3 修饰核心生物钟蛋白（Bmal1、Clock、Per、Cry 和 Rev-erbα）。GSK3 的磷酸化导致生物钟激活蛋白（Bmal1 和 Clock）失活和降解，反之亦然，生物钟抑制蛋白（Per 和 Rev-erbα）激活和核转位，除了 Cry 蛋白，它可能参与生物钟的微调。功能上，GSK3 似乎是昼夜节律和抗氧化防御交叉调节的枢纽之一。在这里，我们介绍了最强大的细胞抗氧化机制 Nrf2 系统与哺乳动物生物节律调节系统之间的串扰数据，包括 GSK3 过表达和敲除对 Nrf2 信号的影响。了解将内稳态维持和细胞对氧化应激反应联系起来的调控级联之间的相互作用，将有助于阐明衰老和长寿的分子机制。
