Koga Tomoaki, Suico Mary Ann, Shimasaki Shogo, Watanabe Eriko, Kai Yukari, Koyama Kosuke, Omachi Kohei, Morino-Koga Saori, Sato Takashi, Shuto Tsuyoshi, Mori Kazutoshi, Hino Shinjiro, Nakao Mitsuyoshi, Kai Hirofumi
From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan, Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
J Biol Chem. 2015 Dec 18;290(51):30366-74. doi: 10.1074/jbc.M115.664169. Epub 2015 Oct 23.
Sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase, plays crucial roles in various biological processes including longevity, stress response, and cell survival. Endoplasmic reticulum (ER) stress is caused by dysfunction of ER homeostasis and exacerbates various diseases including diabetes, fatty liver, and chronic obstructive pulmonary disease. Although several reports have shown that SIRT1 negatively regulates ER stress and ER stress-induced responses in vitro and in vivo, the effect of ER stress on SIRT1 is less explored. In this study, we showed that ER stress induced SIRT1 expression in vitro and in vivo. We further determined the molecular mechanisms of how ER stress induces SIRT1 expression. Surprisingly, the conventional ER stress-activated transcription factors XBP1, ATF4, and ATF6 seem to be dispensable for SIRT1 induction. Based on inhibitor screening experiments with SIRT1 promoter, we found that the PI3K-Akt-GSK3β signaling pathway is required for SIRT1 induction by ER stress. Moreover, we showed that pharmacological inhibition of SIRT1 by EX527 inhibited the ER stress-induced cellular death in vitro and severe hepatocellular injury in vivo, indicating a detrimental role of SIRT1 in ER stress-induced damage responses. Collectively, these data suggest that SIRT1 expression is up-regulated by ER stress and contributes to ER stress-induced cellular damage.
沉默调节蛋白1（SIRT1）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的组蛋白脱乙酰酶，在包括寿命、应激反应和细胞存活等多种生物学过程中发挥关键作用。内质网（ER）应激是由内质网稳态功能障碍引起的，并加剧包括糖尿病、脂肪肝和慢性阻塞性肺疾病在内的各种疾病。尽管有几份报告表明SIRT1在体外和体内对ER应激及ER应激诱导的反应起负调节作用，但ER应激对SIRT1的影响研究较少。在本研究中，我们表明ER应激在体外和体内均可诱导SIRT1表达。我们进一步确定了ER应激诱导SIRT1表达的分子机制。令人惊讶的是，传统的ER应激激活转录因子XBP1、ATF4和ATF6似乎对于SIRT1的诱导并非必需。基于对SIRT1启动子的抑制剂筛选实验，我们发现PI3K-Akt-GSK3β信号通路是ER应激诱导SIRT1所必需的。此外，我们表明EX527对SIRT1的药理学抑制在体外抑制了ER应激诱导的细胞死亡，在体内抑制了严重的肝细胞损伤，表明SIRT1在ER应激诱导的损伤反应中起有害作用。总体而言，这些数据表明SIRT1表达受ER应激上调，并导致ER应激诱导的细胞损伤。
