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.
Related publications:
1. Liu B, Salgado OC, Singh S, Hippen KL, Maynard JC, Burlingame AL, Ball LE, Blazar BR, Farrar MA, Hogquist KA, Ruan HB. (2019). The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nature Communications. 10:354.
2. Ruan HB, Ma Y, Torres S, Zhang B, Feriod C, Heck RM, Qian K, Fu M, Li X, Nathanson MH, Bennett AM, Nie Y, Ehrlich BE, Yang X. (2017). Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes & Development. 31(16): 1655-1665.
3. Ruan HB, Nie Y, Yang, X. (2013). Regulation of protein degradation by O-GlcNAcylation: crosstalk with ubiquitination. Molecular & Cellular Proteomics. 12(12): 3489-97.
4. Ruan HB, Singh JP, Li MD, Wu J, Yang, X. (2013). Cracking the O-GlcNAc code in metabolism. Trends in Endocrinology & Metabolism. 24(6): 301-309.
5. Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, Zhao L, Bennett AM, Samuel VT, Wu J, Yates JR, Yang X. (2012). O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metabolism. 16(2): 226-237.
The HBP pathway and O-GlcNAcylation.