Kaasik, K., Kivimäe, S., Allen, J.J., Chalkley, R.J., Huang, Y., Baer, K., Kissel, H., Burlingame, A.L., Shokat, K.M., Ptáček, L.J., Fu, Y.H. (2013). Glucose Sensor O-GlcNAcylation Coordinates with Phosphorylation to Regulate Circadian Clock.  Cell Metab. 17(2): 291--302.

FBrf0220792

Research paper

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.

PMC3597447 (PMC) (EuropePMC)