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

• Published in: Cell metabolism Vol. 17; no. 2; pp. 291 - 302
• Main Authors: Kaasik, Krista, Kivimäe, Saul, Allen, Jasmina J., Chalkley, Robert J., Huang, Yong, Baer, Kristin, Kissel, Holger, Burlingame, Alma L., Shokat, Kevan M., Ptáček, Louis J., Fu, Ying-Hui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.02.2013
• Subjects: Acetylglucosamine - metabolism; Adenosine Triphosphate - analogs & derivatives; Amino Acid Sequence; Animals; Circadian Clocks; CLOCK Proteins - chemistry; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Drosophila melanogaster - metabolism; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Glucose - metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycosylation; Humans; Mice; Molecular Sequence Data; N-Acetylglucosaminyltransferases - chemistry; N-Acetylglucosaminyltransferases - metabolism; Phosphorylation; Substrate Specificity; Transcription, Genetic; Transfection
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.12.017

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. ► O-GlcNAc transferase and GSK3β exhibit reciprocal regulation ► O-GlcNAcylation modulates the functions of molecular clock components ► O-GlcNAcylation and molecular clock reciprocally regulate each other ► Competition between O-GlcNAcylation and phosphorylation regulates clock speed