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Glucose Sensor O-GlcNAcylation Coordinates with Phosphorylation to Regulate Circadian Clock

2013; Cell Press; Volume: 17; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2012.12.017

1932-7420

Krista Kaasik, Saul Kivimäe, Jasmina J. Allen, Robert J. Chalkley, Yong Huang, Kristin Baer, Holger Kissel, Alma L. Burlingame, Kevan M. Shokat, Louis J. Ptáček, Ying‐Hui Fu,

Carbohydrate Chemistry and Synthesis

Posttranslational modifications play central roles in myriad biological pathways including circadian regulation. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. Modulating O-GlcNAcylation levels alter circadian period length in both mice and Drosophila; conversely, protein O-GlcNAcylation is circadianly regulated. Central clock proteins, Clock and Period, are reversibly modified by O-GlcNAcylation to regulate their transcriptional activities. In addition, O-GlcNAcylation of a region in PER2 known to regulate human sleep phase (S662-S674) competes with phosphorylation of this region, and this interplay is at least partly mediated by glucose levels. Together, these results indicate that O-GlcNAcylation serves as a metabolic sensor for clock regulation and works coordinately with phosphorylation to fine-tune circadian clock.