Protein O-GlcNAcylation in Immunometabolism


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 developmental, cardiometabolic, 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 adult stem cell fate, metabolic physiology, and immune responses

Related publications:

1. Zhao M, Ren K, Xiong X, Xin Y, Zou Y, Maynard JC, Kim A, Battist AP, Koneripalli N, Wang Y, Chen Q, Xin R, Yang C, Huang R, Yu J, Huang Z, Zhang Z, Wang H, Wang D, Xiao Y, Salgado OC, Jarjour NN, Hogquist KA, Revelo XS, Burlingame AL, Gao X, von Moltke J, Lin Z, Ruan HB. (2022). Epithelial STAT6 O-GlcNAcylation drives anti-helminth immunity via a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity. 55(4): 623–638. DOI: 10.1016/j.immuni.2022.03.009.
2. Zhang Z, Salgado OC, Liu B, Moazzami Z, Hogquist KA, Farrar MA, Ruan HB. (2022). An OGT-STAT5 axis in regulatory T cells controls energy and iron metabolism. Frontiers in Immunology. 13:874863. DOI: 10.3389/fimmu.2022.874863.
3. 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.

HBP pathway

The HBP pathway and O-GlcNAcylation.