Disruption of O-GlcNAc Cycling in C. elegans Perturbs Nucleotide Sugar Pools and Complex Glycans

Salil K Ghosh1, Michelle R Bond1, Dona C Love1

  • 1Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD , USA.

Frontiers in Endocrinology
|December 16, 2014
PubMed

Insights

Altering O-linked beta-N-acetylglucosamine (O-GlcNAc) modification impacts nucleotide sugar levels and gene expression. This highlights O-GlcNAc

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • O-linked beta-N-acetylglucosamine (O-GlcNAc) is a ubiquitous post-translational modification regulating cellular processes.
  • The hexosamine biosynthetic pathway (HBP) produces UDP-GlcNAc, essential for O-GlcNAc and other glycosylation events.
  • Perturbations in O-GlcNAc cycling can influence nutrient sensing and metabolic pathways.

Purpose of the Study:

  • To investigate the biochemical consequences of disrupting the O-GlcNAc pathway in C. elegans.
  • To analyze the effects of O-GlcNAc transferase (ogt-1) and O-GlcNAcase (oga-1) mutations on nucleotide sugar levels and gene expression.

Main Methods:

  • Analysis of ogt-1 null C. elegans mutants.
  • Measurement of steady-state levels of UDP-GlcNAc, UDP-GalNAc, and UDP-glucose.
  • Quantitative analysis of gene transcript levels involved in HBP and trehalose metabolism.
  • Assessment of glycan profiles, including PNGase-sensitive and insensitive glycans.

Main Results:

  • ogt-1 null animals exhibited significantly elevated UDP-GlcNAc/UDP-GalNAc and UDP-glucose levels.
  • Transcripts for key HBP and trehalose metabolism genes were upregulated in ogt-1 null mutants.
  • While N-linked glycans remained unchanged, O-linked glycans, glycolipids, and glycopolymers were altered in ogt-1 and oga-1 mutants.

Conclusions:

  • Disruption of O-GlcNAcylation alters nucleotide sugar production and the transcription of glycan-processing enzymes.
  • Changes in O-GlcNAc modification impact overall glycan composition.
  • O-GlcNAc cycling plays a significant role in nutrient sensing and metabolic regulation.

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