Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.

Area of Science:

• Biochemistry
• Chronobiology
• Molecular Biology

Background:

• Posttranslational modifications are crucial for biological pathways, including circadian regulation.
• Understanding the interplay between metabolic status and circadian rhythms is essential.

Purpose of the Study:

• To investigate the role of O-GlcNAcylation in circadian clock regulation.
• To identify novel substrates and regulatory mechanisms of GSK3β within circadian pathways.

Main Methods:

• Circadian proteomic analysis was used to identify key protein interactions and modifications.
• Experiments were conducted in both mouse and Drosophila models to assess circadian period length.
• Specific protein modifications, including O-GlcNAcylation and phosphorylation, were analyzed in central clock proteins.

Main Results:

• O-GlcNAc transferase (OGT) was identified as a substrate of GSK3β, revealing reciprocal regulation between these enzymes.
• Modulating O-GlcNAcylation levels altered circadian period length in mice and Drosophila.
• Protein O-GlcNAcylation was found to be circadianly regulated and affects the transcriptional activity of Clock and Period proteins.
• O-GlcNAcylation of PER2 competes with its phosphorylation, influenced by glucose levels, impacting human sleep phase regulation.

Conclusions:

• O-GlcNAcylation acts as a metabolic sensor, integrating nutrient status with circadian clock function.
• The interplay between O-GlcNAcylation and phosphorylation fine-tunes circadian rhythms.
• These findings provide new insights into the molecular mechanisms governing circadian timekeeping and its metabolic regulation.