Post-translational modifications (PTMs) are versatile regulatory nodes integrating metabolic and immunological signals for proper protein function and cellular homeostasis. Thousands of intracellular proteins are modified by a single O-linked N-Acetylglucosamine (O-GlcNAc) moiety at serine or threonine residues, termed O-GlcNAcylation. This dynamic and reversible modification, mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a key regulator of diverse cellular processes such as signal transduction, transcription, translation, and proteasomal degradation. Perturbations in protein O-GlcNAcylation are implicated in cardiometabolic diseases and immune disorders.
The donor substrate UDP-GlcNAc is derived from nutrients through the hexosamine biosynthetic pathway (HBP). Cellular levels of UDP-GlcNAc and protein O-GlcNAcylation not only fluctuate with nutrient availability (glucose, free fatty acids, uridine, and glutamine), but also respond to microbial infections, inflammatory signals, and cellular stress. Currently, we are investigating how nutrients integrate with hormonal and environmental cues to regulate protein O-GlcNAcylation in controlling metabolic physiology and immune responses.
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