Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies.

Nutrient Regulation of Signaling, Transcription, and Cell Physiology by O-GlcNAcylation

“…Strong evidence from many laboratories support a role for the hexosamine biosynthetic pathway (HBP), and its end product UDP-GlcNAc, as important nutrient sensors (Bond and Hanover, 2013; Hart et al, 2011; Vaidyanathan et al, 2014). The biosynthesis of UDP-GlcNAc is regulated by nearly every major metabolic pathway (Figure 1a).…”

“…This short review cannot summarize all the extensive work about O -GlcNAcylation of proteins and their regulation (we refer interested readers to recent comprehensive reviews: Bond and Hanover, 2013; Hart et al, 2011; Ma and Hart, 2013; Ruan et al, 2013; Vaidyanathan et al, 2014). Here we discuss only very recent findings that illustrate how OGT and O -GlcNAcylation regulate key downstream effectors to modulate cell physiology in response to nutrients.…”

Posttranscriptional regulation of uridine diphosphate glucuronosyltransferases

“…Interestingly, while O-linked glycosylation has not yet been confirmed as a posttranscriptional regulatory element for UGT activity, this mechanism competes with serine/ threonine phosphorylation [79]. Because both serine/threonine phosphorylation and N-linked glycosylation are important posttranscriptional regulatory element for UGTs, the role of O-linked glycosylation alone, and with PKC regulation should be pursued.…”

N-acetylglucosamine modification in the lumen of the endoplasmic reticulum

“…Intracellular OGlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) [3][4][5][6]. O-GlcNAc modification regulates many cellular processes [7] such as transcriptional control [8], chromatin remodeling [9][10][11], signal transduction [12], cell differentiation [13][14][15], and nutrient sensing [16,17]. OGT is the only enzyme that catalyzes the O-GlcNAcylation of intracellular proteins [18].…”