Yuan Gongsheng, Hua Bingxuan, Cai Tingting, Xu Lirong, Li Ermin, Huang Yiqing, Sun Ning, Yan Zuoqin, Lu Chao, Qian Ruizhe
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, 200032, China.
Aging (Albany NY). 2017 Dec 22;9(12):2647-2665. doi: 10.18632/aging.101353.
Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood. Here, we show that Clock-mediated Pdia3 expression is required to sustain reactive oxidative reagents and ER stress. First, ER stress and ROS are strongly activated in the liver tissue of mutant mice, which exhibit a significant aging phenotype. Next, transcription of Pdia3 is mediated by the circadian gene Clock, but this process is affected by the mutant due to the low affinity of the E-box motif in the promoter. Finally, ablation of Pdia3 with siRNA causes ER stress with sustained phosphorylation of PERK and eIF1α, resulting in exaggerated up-regulation of UPR target genes and increased apoptosis as well as ROS. Moreover, the combined effects result in an imbalance of cell homeostasis and ultimately lead to cell damage and senescence. Taken together, this study identified the circadian gene Clock as a regulator of ER stress and senescence, which will provide a reference for the clinical prevention of aging.
越来越多的证据表明，昼夜节律基因在大多数哺乳动物中调节细胞损伤和衰老。内质网（ER）应激和活性氧（ROS）在许多生物体中调节寿命。然而，生物钟与生物体中这两个应激过程之间关系的具体机制尚不清楚。在此，我们表明，Clock介导的Pdia3表达是维持活性氧化试剂和内质网应激所必需的。首先，内质网应激和ROS在突变小鼠的肝脏组织中被强烈激活，这些小鼠表现出明显的衰老表型。其次，Pdia3的转录由昼夜节律基因Clock介导，但由于启动子中E-box基序的低亲和力，该过程受到突变的影响。最后，用siRNA敲除Pdia3会导致内质网应激，伴有PERK和eIF1α的持续磷酸化，导致未折叠蛋白反应（UPR）靶基因过度上调、细胞凋亡增加以及ROS增加。此外，这些联合效应导致细胞稳态失衡，最终导致细胞损伤和衰老。综上所述，本研究确定昼夜节律基因Clock是内质网应激和衰老的调节因子，这将为衰老的临床预防提供参考。
