O-GlcNAc Signaling Entrains the Circadian Clock by Inhibiting BMAL1/CLOCK Ubiquitination

Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked β-D-N-acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripher...

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Bibliographic Details
Published in:Cell metabolism 2013-02, Vol.17 (2), p.303-310
Main Authors: Li, Min-Dian, Ruan, Hai-Bin, Hughes, Michael E., Lee, Jeong-Sang, Singh, Jay P., Jones, Steven P., Nitabach, Michael N., Yang, Xiaoyong
Format: Article
Language:English
Subjects:
Acetylglucosamine - metabolism
Animals
ARNTL Transcription Factors - genetics
ARNTL Transcription Factors - metabolism
Cell Line, Tumor
Circadian Clocks - genetics
CLOCK Proteins - genetics
CLOCK Proteins - metabolism
Gene Expression Regulation
Glucose - metabolism
Homeostasis
Humans
Liver - enzymology
Mice
N-Acetylglucosaminyltransferases - metabolism
Protein Stability
Signal Transduction - genetics
Ubiquitination - genetics
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Summary:Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked β-D-N-acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripheral clock oscillation. O-GlcNAc transferase (OGT) promotes expression of BMAL1/CLOCK target genes and affects circadian oscillation of clock genes in vitro and in vivo. Both BMAL1 and CLOCK are rhythmically O-GlcNAcylated, and this protein modification stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination. In vivo analysis of genetically modified mice with perturbed hepatic OGT expression shows aberrant circadian rhythms of glucose homeostasis. These results establish the counteraction between O-GlcNAcylation and ubiquitination as a key mechanism that regulates the circadian clock and suggest a crucial role for O-GlcNAc signaling in transducing nutritional signals to the core circadian timing machinery. [Display omitted] ► The hexosamine/O-GlcNAc pathway regulates cellular clock oscillation ► OGT promotes expression of BMAL1/CLOCK target genes in cultured cells and liver ► Rhythmic O-GlcNAcylation stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination ► Hepatic manipulation of OGT perturbs the diurnal rhythm of glucose homeostasis
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2012.12.015