Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, South Korea.
Korea Institute of Molecular Medicine and Nutrition, Seoul, South Korea.
FASEB J. 2019 Feb;33(2):2422-2434. doi: 10.1096/fj.201800836R. Epub 2018 Sep 27.
The importance of proteostasis in preventing cellular senescence has been well recognized. However, the exact mechanism by which the loss of proteostasis or endoplasmic reticulum (ER) stress induces cellular senescence remains unclear. We report that ER stress mediates cellular senescence through the activating transcription factor (ATF)6α branch of the unfolded protein response (UPR). Cellular senescence was induced by the abrogation of neighbor of breast cancer (BRCA)1 gene (NBR1). NBR1 abrogation-induced senescence was p53 dependent and observed in both transformed and nontransformed human cell lines: MCF-7, Caki-1, and MRC-5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidase was activated in turn by p38, and the resulting oxidative stress triggered ER stress. It was found that ER stress mediated cellular senescence through the UPR sensor ATF6α. Knockdown of ATF6α prevented senescence, whereas ATF6α overexpression triggered it. The transcriptional activity of ATF6α was important. The ER stress-ATF6α axis also mediated cellular senescence induced by H-RasV12 overexpression and UV irradiation, suggesting a common role of this axis in senescence induction. In summary, we presented an evidence for the novel role of the ER stress-ATF6α axis in cellular senescence.-Kim, H. S., Kim, Y., Lim, M. J., Park, Y.-G., Park, S. I., Sohn, J. The p38-activated ER stress-ATF6α axis mediates cellular senescence.
细胞衰老过程中蛋白质平衡的重要性已得到充分认识。然而，确切的机制，即蛋白质平衡的丧失或内质网（ER）应激诱导细胞衰老仍然不清楚。我们报告 ER 应激通过未折叠蛋白反应（UPR）的激活转录因子（ATF）6α分支介导细胞衰老。细胞衰老通过乳腺癌基因 1（BRCA1）基因（NBR1）的缺失来诱导。NBR1 缺失诱导的衰老依赖于 p53，并在转化和非转化的人类细胞系中观察到：MCF-7、Caki-1 和 MRC-5。NBR1 与 p38 MAPK 结合，优先与活性形式结合，并且在 NBR1 缺失后，p38 的活性增加。NADPH 氧化酶依次被 p38 激活，由此产生的氧化应激引发 ER 应激。研究发现，ER 应激通过 UPR 传感器 ATF6α介导细胞衰老。ATF6α 的敲低阻止了衰老，而 ATF6α 的过表达则引发了衰老。ATF6α 的转录活性很重要。ER 应激-ATF6α 轴也介导了 H-RasV12 过表达和 UV 照射诱导的细胞衰老，这表明该轴在衰老诱导中具有共同作用。总之，我们提出了 ER 应激-ATF6α 轴在细胞衰老中的新作用的证据。-金，H.S.，金，Y.，林，M.J.，朴，Y.-G.，朴，S.I.，宋，J.。p38 激活的 ER 应激-ATF6α 轴介导细胞衰老。
