Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Abstract

O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (O-GlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced O-GlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

Fig. 1

The hexosamine biosynthetic pathway provides the donor substrate for O-GlcNAcylation and other types of protein glycosylation. Upon entry into the cell, a small percentage of Glucose (2–5 % in adipocytes) is directed into the hexosamine biosynthetic pathway and converted into UDP-GlcNAc via glutamine:fructose-6-phosphate amidotransferase (GFAT), glucosamine-6-phosphate acetyltransferase (EMeg32), N-acetylglucosamine-phosphate mutase (pgm3), and UDP-GlcNAc pyrophosphorylase (uap1). OGT catalyzes the addition of the glycoside to yield O-GlcNAcylated nuclear, cytoplasmic, and mitochondrial proteins, whereas the enzyme O-GlcNAcase catalyzes the removal O-GlcNAc from proteins. O-GlcNAc-modified proteins are involved in many cellular processes including the cellular stress response. HK hexokinase, G6P-I glucose 6-phosphate isomerase, Glc glucose, NAc N-acetyl

Fig. 2

O-GlcNAc is involved in the cellular stress response. Glucose and glucosamine can enter cells via glucose transporters and are directed towards the HBP for conversion to UDP-GlcNAc. O-GlcNAcylation of key proteins is essential for maintaining cellular homeostasis and promoting survival during stress and injury. Key survival pathways modulated by O-GlcNAc include: (1) the PI3K/Akt pathway, (2) heat shock protein expression, (3) calcium homeostasis, (4) reactive oxygen species regulation, (5) mitochondrial dynamics, (6) inflammation, and (7) PTM interplay. Note that proteins are shown as light blue squares, O-GlcNAc as green circles, and phosphates as orange circles. Arrows denote activation, whereas blunt ends denote inhibition. OGA O-GlcNAcase, OGT O-GlcNAc transferase