O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination.

Authors:
Dr. Min-Dian Li, PhD
Dr. Min-Dian Li, PhD
Harvard TH Chan School of Public Health
Postdoctoral Fellow
Cellular and Molecular Physiology
Boston, MA | United States
Hai-Bin Ruan
Hai-Bin Ruan
United States
Michael E Hughes
Michael E Hughes
Yale School of Medicine
New Haven | United States
Jeong-Sang Lee
Jeong-Sang Lee
South Korea
Jay P Singh
Jay P Singh
University of Oxford
United Kingdom
Steven P Jones
Steven P Jones
Institute of Molecular Cardiology
Louisville | United States
Michael N Nitabach
Michael N Nitabach
Yale University School of Medicine
New Haven | United States
Xiaoyong Yang
Xiaoyong Yang
Yale University School of Medicine
New Haven | United States

Cell Metab 2013 Feb;17(2):303-10

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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.

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Source
http://dx.doi.org/10.1016/j.cmet.2012.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647362PMC

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February 2013
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