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

Cell Metab. 2013 Feb 5;17(2):291-302. doi: 10.1016/j.cmet.2012.12.017.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Adenosine Triphosphate / analogs & derivatives
  • Amino Acid Sequence
  • Animals
  • CLOCK Proteins / chemistry
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Clocks*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / 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

Substances

  • Drosophila Proteins
  • Adenosine Triphosphate
  • CLOCK Proteins
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Glucose
  • Acetylglucosamine