Synopsis 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.

TGF-β1 (transforming growth factor-β1) plays a central role in regulating proliferation, migration and differentiation of dental pulp cells during the repair process after tooth injury. Our previous study showed that p38 mitogen-activated protein kinase may act downstream of TGF-β1 signalling to effect the differentiation of dental pulp cells. However, the molecular mechanisms that trigger and regulate the process remain to be elucidated. TGF-β1 interacts with signalling pathways such as Wnt/β-catenin and Rho to induce diverse biological effects. TGF-β1 activates β-catenin signalling, increases β-catenin nuclear translocation and interacts with LEF/TCF to regulate gene expression. Morphologic changes in response to TGF-β1 are associated with activation of Rho GTPases, but are abrogated by inhibitors of Rho-associated kinase, a major downstream target of Rho. These results suggest that the Wnt/β-catenin and Rho pathways may mediate the downstream events of TGF-β1 signalling.