Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation.
Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation.
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DOI：
10.1042/bj20101293
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Ouyang HJ
中科院分区：
文献类型：
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作者：
Wang FM;Chen YJ;Ouyang HJ
X盒结合蛋白1(XBP1)是未折叠蛋白反应(UPR)的关键调节因子，参与了广泛的病理生理过程。XBP1(XBP1s)信使RNA的活性/剪接形式是由IRE1在UPR过程中从非剪接形式产生的。然而，XBP1的翻译后调节在很大程度上仍然未知。在这里，我们证明了XBP1s是分别由p300和SIRT1介导的乙酰化和去乙酰化的靶点。P300增强XBP1s的乙酰化和蛋白质稳定性，并增强XBP1s的转录活性。SIRT1去乙酰化XBP1s并抑制XBP1s的转录活性。SIRT1基因缺失可增强HEK293细胞中XBP1s介导的荧光素酶报告活性，并上调内质网应激下小鼠胚胎成纤维细胞中XBP1s靶基因的表达。与支持细胞在内质网应激下存活的XBP1一致，Sirt1−/−MEF与Sirt1+/+MEF相比，对内质网应激诱导的细胞死亡表现出更大的抵抗能力。综上所述，这些结果表明，乙酰化/去乙酰化是控制XBP1蛋白水平和转录活性的重要翻译后机制。本研究为SIRT1调控UPR信号的分子机制提供了新的视角。
X-box-binding protein 1 (XBP1) is a key modulator of unfolded protein response (UPR), which is involved in a wide range of pathological and physiological processes. The active/spliced form of XBP1 (XBP1s) messenger RNA is generated from unspliced form by IRE1 during UPR. However, post-translational modulation of XBP1s remains largely unknown. Here, we demonstrate that XBP1s is a target of acetylation and deacetylation mediated by p300 and SIRT1 respectively. p300 increases acetylation and protein stability of XBP1s, and enhances the transcriptional activity of XBP1s. SIRT1 deacetylates XBP1s and inhibits the transcriptional activity of XBP1s. Deficiency of SIRT1 enhances the XBP1s-mediated luciferase reporter activity in HEK293 cells and the upregulation of XBP1s target gene expression under ER stress in mouse embryonic fibroblasts (MEFs). Consistent with XBP1s favoring cell survival under ER stress, Sirt1−/− MEFs display a greater resistance to the ER stress-induced apoptotic cell death compared with Sirt1+/+ MEFs. Taken together, these results suggest that acetylation/deacetylation constitutes an important post-translational mechanism in controlling protein levels as well as transcriptional activity of XBP1s. This study provides a novel insight into molecular mechanisms by which SIRT1 regulates UPR signaling.