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

  • Author(s): 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
  • et al.

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.

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