Disruption of O-GIcNAc cycling in C. elegans perturbs nucleotide sugar pools and complex glycans

The carbohydrate modification of serine and threonine residues with O-linked beta-N-acetylglucosamine (O-GIcNAc) is ubiquitous and governs cellular processes ranging from cell signaling to apoptosis. The O-GIcNAc modification along with other carbohydrate modifications, including N-linked and O-linked glycans, glycolipids, and sugar polymers, all require the use of the nucleotide sugar UDP-GIcNAc, the end product of the hexosamine biosynthetic pathway (HBP). In this paper, we describe the biochemical consequences resulting from perturbation of the O-GIcNAc pathway in C. elegans lacking O-GIcNAc transferase and O-GIcNAcase activities. In ogt-1 null animals, steady-state levels of UDP-GIcNAc/UDP-GaINAc and UDP-glucose were substantially elevated. Transcripts of genes encoding for key members in the HBP (gfat-2, gna-2, C36A4.4) and trehalose metabolism (tre-1, tre-2, tps-2) were elevated in ogt-1 null animals. While there is no evidence to suggest changes in the profile of N-linked glycans in the ogt-1 and oga-1 mutants, glycans insensitive to PNGase digestion (including O-linked glycans, glycolipids, and glycopolymers) were altered in these strains. Our data support that changes in O-GIcNAcylation alters nucleotide sugar production, overall glycan composition, and transcription of genes encoding glycan processing enzymes. These data along with our previous findings that disruption in O-GIcNAc cycling alters macronutrient storage underscores the noteworthy influence this posttranslational modification plays in nutrient sensing.