title: Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.
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.
authors: Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.
authors: Krista
authors: K
authors: Kaasik
authors: Saul
authors: S
authors: Kivimäe
authors: Jasmina J
authors: JJ
authors: Allen
authors: Robert J
authors: RJ
authors: Chalkley
authors: Yong
authors: Y
authors: Huang
authors: Kristin
authors: K
authors: Baer
authors: Holger
authors: H
authors: Kissel
authors: Alma L
authors: AL
authors: Burlingame
authors: Kevan M
authors: KM
authors: Shokat
authors: Louis J
authors: LJ
authors: Ptáček
authors: Ying-Hui
authors: YH
authors: Fu
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D000818:Animals; D056926:CLOCK Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D013379:Substrate Specificity; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; D000255:Adenosine Triphosphate; D056926:CLOCK Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D005947:Glucose; D000117:Acetylglucosamine
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