The NAD+-dependent protein deacetylase activity of SIRT1 is regulated by its oligomeric status

• Published in: Scientific reports 2012-09, Vol.2 (1), p.640
• Main Authors: Guo, Xiumei, Kesimer, Mehmet, Tolun, Gökhan, Zheng, Xunhai, Xu, Qing, Lu, Jing, Sheehan, John K., Griffith, Jack D., Li, Xiaoling
• Format: Article
• Language: English
• Subjects: 631/337; 631/337/458; 631/57; 631/80/86; Animals; Cell Survival; Cellular stress response; Energy metabolism; Environmental regulations; Environmental stress; Enzyme Activation; Heat-Shock Response; HEK293 Cells; Humanities and Social Sciences; Humans; Kinases; Mice; multidisciplinary; NAD; Phosphorylation; Protein Multimerization; Protein Processing, Post-Translational; Protein Structure, Quaternary; Proteins; Science; SIRT1 protein; Sirtuin 1 - chemistry; Sirtuin 1 - metabolism; Sirtuin 1 - ultrastructure; Stress response; Tumor Suppressor Protein p53 - chemistry
• ISSN: 2045-2322
• DOI: 10.1038/srep00640

SIRT1, a NAD + -dependent protein deacetylase, is an important regulator in cellular stress response and energy metabolism. While the list of SIRT1 substrates is growing, how the activity of SIRT1 is regulated remains unclear. We have previously reported that SIRT1 is activated by phosphorylation at a conserved Thr522 residue in response to environmental stress. Here we demonstrate that phosphorylation of Thr522 activates SIRT1 through modulation of its oligomeric status. We provide evidence that nonphosphorylated SIRT1 protein is aggregation-prone in vitro and in cultured cells. Conversely, phosphorylated SIRT1 protein is largely in the monomeric state and more active. Our findings reveal a novel mechanism for environmental regulation of SIRT1 activity, which may have important implications in understanding the molecular mechanism of stress response, cell survival and aging.