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 Clock(Delta 19) 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 Clock(Delta 19) 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 eIF1 alpha, 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.
[1]Fudan Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Res Ctr Aging & Med, Shanghai Key Lab Clin Geriatr Med, Shanghai 200032, Peoples R China.
[3]Fudan Univ, Zhongshan Hosp, Dept Orthoped, Shanghai 200032, Peoples R China.
[4]Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China.
[5]Fudan Univ, Huadong Hosp, Shanghai Med Coll, Dept Gastroenterol, Shanghai 200040, Peoples R China.
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