PMID: 23395175

 

    Legend: Sugar

Title : Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock

Abstract :

1. Posttranslational modifications play central roles in myriad biological pathways including circadian regulation
2. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-d ependent pathways and identified O-GlcNAc transferase ( OGT ) as a substrate of GSK3β.
3. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation
4. Modulating O-GlcNAcylation levels alter circadian period length in both mice and Drosophila; conversely, protein O-GlcNAcylation is circadianly regulated
5. Central clock proteins , Clock and Period, are reversibly modified by O-GlcNAcylation to regulate their transcriptional activities
6. 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.
7. 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