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.
Bibliographical noteFunding Information:
We thank P. Sassone-Corsi for Myc-BMAL1 and Myc-CLOCK constructs, K. Lamia for pGL3- Per2 , and S. Panda for U2OS-B6 cell line. We are grateful to Clifford Slayman and Yao Wu for inspiring discussions. This work was supported by NIH R01 DK089098, P01 DK057751, American Diabetes Association, and Ellison Medical Foundation to X.Y.; NIH R21 NS058330, R01 NS055035, R01 NS056443, and R01 GM098931 to M.N.N.; NIH R01 HL083320, R01 HL094419, P01 HL078825, and P20 RR024489 to S.P.J.; CSC-Yale World Scholars Program scholarship to M.-D.L.; Brown-Coxe fellowship to H.-B.R.; and NIH F32GM096577 to M.E.H.