The post-translational modification O-GlcNAc is a sensor and regulator of metabolism

Abstract

Cells must rapidly adapt to changes in nutrient conditions through responsive signalling cascades to maintain homeostasis. One of these adaptive pathways results in the post-translational modification of proteins by O-GlcNAc. O-GlcNAc modifies thousands of nuclear and cytoplasmic proteins in response to nutrient availability through the hexosamine biosynthetic pathway. O-GlcNAc is highly dynamic and can be added and removed from proteins multiple times throughout their life cycle, setting it up to be an ideal regulator of cellular processes in response to metabolic changes. Here, we describe the link between cellular metabolism and O-GlcNAc, and we explore O-GlcNAc's role in regulating cellular processes in response to nutrient levels. Specifically, we discuss the mechanisms of elevated O-GlcNAc levels in contributing to diabetes and cancer, as well as the role of decreased O-GlcNAc levels in neurodegeneration. These studies form a foundational understanding of aberrant O-GlcNAc in human disease and provide an opportunity to further improve disease identification and treatment.

Keywords: O-GlcNAc; metabolism; modifications; post-translational; regulators; sensor.

Figure 1.

2–3% of glucose entering the cell is diverted from glycolysis into the hexosamine biosynthetic pathway (HBP). The end product of the HBP is UDP-GlcNAc, the high energy donor sugar used by OGT to transfer O-GlcNAc onto protein substrates. When OGA removes O-GlcNAc from proteins, GlcNAc can then by recycled through the GlcNAc salvage pathway which eventually converges with the HBP.

Figure 2.

(a) Normal insulin signalling and (b) insulin signalling inhibited by O-GlcNAc. O-GlcNAc regulates insulin signalling through translocation of OGT to the plasma membrane during prolonged insulin signalling. At the plasma membrane, OGT then modifies multiple proteins including AKT. O-GlcNAcylation of AKT reduces its activity, decreasing the phosphorylation of its substrates and affecting multiple downstream signalling cascades.

Figure 3.

Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are implicated by soluble proteins in neurons, tau and α-Syn, that undergo nucleation to form oligomers. These oligomers then undergo molecular rearrangement and rapid extension to form protein aggregates. O-GlcNAc modifies tau and α-Syn at multiple sites and inhibits the nucleation and extension steps to slow amyloid formation.