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

Cuifang Han,Wenyi Mi,Minghui Shi,Feng Han,Jiahui Sun,Hui Shan,Qianhong Gong,Yuchao Gu,Xinzhi Lu,Wengong Yu,Xinling Zhang

doi:10.1038/s41467-017-01654-6

Cuifang Han, Wenyi Mi + Show 9 more

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https://doi.org/10.1038/s41467-017-01654-6

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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.

Highlights

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 O-GlcNAc transferase (OGT) is the only known cytonuclear enzyme for intracellular protein O-GlcNAcylation, we first investigated whether OGT could bind to SIRT1 to evaluate the possible links between O-GlcNAcylation and SIRT1
We revealed that stress stimuli elevated the O-GlcNAcylation of wild-type SIRT1 (wtSIRT1) more so than that of SIRT1S549A (Fig. 5b)

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Introduction

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. SIRT1 deacetylates and regulates histones as well as a wide range of non-histone substrates, including p537, forkhead (Fox) transcription factors[8], Ku709, peroxisome proliferator-activated receptor γ (PPARγ)[10], PPARγ coactivator1α11, nuclear factor kappa B12, eukaryotic translation initiation factor 2α13, heat shock factor 114, and others. By modulating these proteins, SIRT1 is implicated in a variety of cellular processes, including metabolism[15], DNA repair[16], genomic stability[17], cell cycle[8], cell survival and apoptosis[7], cellular senescence[18], and oncogenesis[19].

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