Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins

Abstract

All animals and plants dynamically attach and remove O-linked beta-N-acetylglucosamine (O-GlcNAc) at serine and threonine residues on myriad nuclear and cytoplasmic proteins. O-GlcNAc cycling, which is tightly regulated by the concerted actions of two highly conserved enzymes, serves as a nutrient and stress sensor. On some proteins, O-GlcNAc competes directly with phosphate for serine/threonine residues. Glycosylation with O-GlcNAc modulates signalling, and influences protein expression, degradation and trafficking. Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration.

Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing

“…Notably, O‐GlcNAc levels respond to nutrient availability both within cells and in vivo in animal models 1b. Transgenic mice overexpressing OGT in fat or muscle tissue exhibit elevated serum leptin and insulin levels in addition to insulin resistance 3.…”

Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation

“…Examples range from interaction between multiple instances of the same PTM at different sites (e.g., prior or priming phosphorylation of site A is necessary for subsequent phosphorylation of site B [14-17]), through hierarchical responses to multiple PTM of the same site [5,37,46], or differential responses to multiple different PTM at different sites [78], and ultimately to crosstalk among different PTM at different sites [79]. A protein with 10 instances of a single PTM could give rise to 1024 (2 n ) different molecular species, but if there are two types of PTM there is the potential to generate 59049 (3 n ) species [46]. The enormity of this molecular diversity would generate a gradient in response that will allow an exquisitely fine control over metabolic activity, signalling, and cellular function [46].…”

“…A protein with 10 instances of a single PTM could give rise to 1024 (2 n ) different molecular species, but if there are two types of PTM there is the potential to generate 59049 (3 n ) species [46]. The enormity of this molecular diversity would generate a gradient in response that will allow an exquisitely fine control over metabolic activity, signalling, and cellular function [46]. …”

“…While a single PTM can modulate protein function, combinatorial and sequential/hierarchical interplay among two or more types of PTM can integrate signals from multiple pathways [6,44,45]. Dynamic interactions among PTM can take place at the same target residue [5,46], or there can be cross-talk between or among multiple residues [47,48]. In some instances the PTM of a specific residue can require a prior (primed) PTM at another site [6,17,49].…”

Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

“…High levels of glucosamine-6-phosphate yield high levels of UDP-N-acetylglucosamine, a substrate for the enzyme O-GlcNAc-transferase. O-GlcNAc-transferase regulates signaling through immunologically relevant receptors (Huang et al, 2007) by transferring O-GlcNAc moieties to serine and threonine residues on cytoplasmic and nuclear proteins (Hart et al, 2007). Thus, strong fluxing through the hexosamine pathway may lead to altered TLR signaling and has been shown to increase the production of TGF-b (Kolm-Litty et al, 1998), and perhaps other HIF-1-regulated genes whose products prevent tolerization of TLR-activated cancer cells.…”