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

Min Dian Li, Hai Bin Ruan, Michael E. Hughes, Jeong Sang Lee, Jay P. Singh, Steven P. Jones, Michael N. Nitabach, Xiaoyong Yang

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)303-310
Number of pages8
JournalCell metabolism
Volume17
Issue number2
DOIs
StatePublished - Feb 5 2013

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