O-GlcNAc cycling: a link between metabolism and chronic disease

Abstract

To maintain homeostasis under variable nutrient conditions, cells rapidly and robustly respond to fluctuations through adaptable signaling networks. Evidence suggests that the O-linked N-acetylglucosamine (O-GlcNAc) posttranslational modification of serine and threonine residues functions as a critical regulator of intracellular signaling cascades in response to nutrient changes. O-GlcNAc is a highly regulated, reversible modification poised to integrate metabolic signals and acts to influence many cellular processes, including cellular signaling, protein stability, and transcription. This review describes the role O-GlcNAc plays in governing both integrated cellular processes and the activity of individual proteins in response to nutrient levels. Moreover, we discuss the ways in which cellular changes in O-GlcNAc status may be linked to chronic diseases such as type 2 diabetes, neurodegeneration, and cancers, providing a unique window through which to identify and treat disease conditions.

Figure 1

O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous nucleocytoplasmic modification added to many protein targets. Two to five percent of total intracellular glucose enters the hexosamine biosynthetic pathway (HBP), and the production of its ultimate product, uridine diphospho (UDP)-GlcNAc, is governed by both enzyme and nutrient availability. O-GlcNAc transferase (OGT) utilizes the activated sugar nucleotide to add O-GlcNAc to target proteins, and O-GlcNAcase (OGA) removes the modification.

Figure 2

O-GlcNAc acts to integrate signals and influences biological processes; its deregulation is correlated with chronic disease. More than 1,000 proteins are known to be modified by O-GlcNAc. O-GlcNAcylation affects (a) protein phosphorylation status as well as downstream cellular signaling and protein activity, (b) targeting to the proteasome as well as proteasome activity, (c) protein stability, (d) transcription, (e) cell cycle and survival, and (f) epigenetic and genomic imprinting.

Figure 3

The O-GlcNAc modification acts as a rheostat on a continuum: Inappropriately high and low levels can have deleterious effects, examples of which are discussed in more detail in the text. Abbreviations: DMII, diabetes mellitus type 2; ROS, reactive oxygen species.