Clock mediates liver senescence by controlling ER stress.
Clock mediates liver senescence by controlling ER stress.
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生物钟通过控制内质网应激介导肝脏衰老
DOI：
10.18632/aging.101353
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发表时间：
2017-12-22
期刊：
影响因子：
--
通讯作者：
Qian R
中科院分区：
文献类型：
--
作者：
Yuan G;Hua B;Cai T;Xu L;Li E;Huang Y;Sun N;Yan Z;Lu C;Qian R
越来越多的证据表明，在大多数哺乳动物中，昼夜节律基因调节细胞损伤和衰老。内质网(ER)应激和活性氧(ROS)调节许多生物体的寿命。然而，生物体中生物钟和这两个应激过程之间关系的具体机制却知之甚少。在这里，我们表明时钟介导的Pdia3表达是维持反应性氧化试剂和内质网应激所必需的。首先，在ClockΔ19突变小鼠的肝脏组织中，ER应激和ROS被强烈激活，表现出显著的衰老表型。接下来，Pdia3的转录是由昼夜节律基因Clock介导的，但由于启动子中E-box基序的低亲和力，这一过程受到ClockΔ19突变的影响。最后，用siRNA去除Pdia3导致内质网应激，导致PERK和eIF1α持续磷酸化，导致UPR靶基因过度上调，细胞凋亡和ROS增加。此外，这些综合作用会导致细胞内环境失衡，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时钟是内质网应激和衰老的调节因子，为临床预防衰老提供参考。
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 ClockΔ19 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 ClockΔ19 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.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
4.3
作者：
Antoch, Marina P.;Gorbacheva, Victoria Y.;Nikitin, Alexander Yu
通讯作者：
Nikitin, Alexander Yu
影响因子：
64.8
作者：
Molinari, M;Helenius, A
通讯作者：
Helenius, A
DOI：
10.1073/pnas.1014523107
发表时间：
2010-11-02
影响因子：
11.1
作者：
Andrews, Jessica L.;Zhang, Xiping;Esser, Karyn A.
通讯作者：
Esser, Karyn A.
影响因子：
64.5
作者：
Green DR;Levine B
通讯作者：
Levine B