O-GlcNAcylation of SIRT1 enhances its deacetylase activity and promotes cytoprotection under stress

• Published in: Nature communications Vol. 8; no. 1; pp. 1491 - 12
• Main Authors: Han, Cuifang, Gu, Yuchao, Shan, Hui, Mi, Wenyi, Sun, Jiahui, Shi, Minghui, Zhang, Xinling, Lu, Xinzhi, Han, Feng, Gong, Qianhong, Yu, Wengong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-11-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/458/1524; 631/80/221; 631/80/86/2366; Acetylation; Acetylglucosamine - metabolism; Animal models; Animals; Antibodies; Apoptosis; Cell Line; Cell Survival; Cytoprotection; Enzyme Activation; Enzymes; Experiments; Female; Gene expression; Genomes; Genotoxicity; Humanities and Social Sciences; Humans; Laboratories; Life Expectancy; Mammals; Metabolism; Mice, Inbred BALB C; Molecular modelling; multidisciplinary; O-GlcNAcylation; Oxidative Stress; Protein Binding; Proteins; Science; Science (multidisciplinary); Serine - metabolism; SIRT1 protein; Sirtuin 1 - chemistry; Sirtuin 1 - metabolism; Stress; Stresses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01654-6

SIRT1 is the most evolutionarily conserved mammalian sirtuin, and it plays a vital role in the regulation of metabolism, stress responses, genome stability, and ageing. As a stress sensor, SIRT1 deacetylase activity is significantly increased during stresses, but the molecular mechanisms are not yet fully clear. Here, we show that SIRT1 is dynamically modified with O-GlcNAc at Ser 549 in its carboxy-terminal region, which directly increases its deacetylase activity both in vitro and in vivo. The O-GlcNAcylation of SIRT1 is elevated during genotoxic, oxidative, and metabolic stress stimuli in cellular and mouse models, thereby increasing SIRT1 deacetylase activity and protecting cells from stress-induced apoptosis. Our findings demonstrate a new mechanism for the activation of SIRT1 under stress conditions and suggest a novel potential therapeutic target for preventing age-related diseases and extending healthspan.
SIRT1 is a stress sensor whose deacetylase activity is increased during cellular stress, but the molecular mechanism is unclear. Here, the authors show that O-GlcNAcylation of SIRT1 is elevated upon different stress stimuli and increases SIRT1 deacetylase activity, protecting cells from stress-induced apoptosis.