ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Abstract

The posttranslational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification. Protein O-GlcNAcylation is rapidly emerging as a key regulator of critical biological processes including nuclear transport, translation and transcription, signal transduction, cytoskeletal reorganization, proteasomal degradation, and apoptosis. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are both major hallmarks of diabetes mellitus and diabetes-related cardiovascular complications. Conversely, there is a growing body of data demonstrating that the acute activation of O-GlcNAc levels is an endogenous stress response designed to enhance cell survival. Reports on the effect of altered O-GlcNAc levels on the heart and cardiovascular system have been growing rapidly over the past few years and have implicated a role for O-GlcNAc in contributing to the adverse effects of diabetes on cardiovascular function as well as mediating the response to ischemic injury. Here, we summarize our present understanding of protein O-GlcNAcylation and its effect on the regulation of cardiovascular function. We examine the pathways regulating protein O-GlcNAcylation and discuss, in more detail, our understanding of the role of O-GlcNAc in both mediating the adverse effects of diabetes as well as its role in mediating cellular protective mechanisms in the cardiovascular system. In addition, we also explore the parallels between O-GlcNAc signaling and redox signaling, as an alternative paradigm for understanding the role of O-GlcNAcylation in regulating cell function. hexosamine biosynthesis; protein O-glycosylation; ␤-N-acetylglucosamine transferase; diabetes mellitus POSTTRANSLATIONAL MODIFICATION (PTM) of proteins is a common mechanism for the modulation of protein function, location, and turnover. Although protein phosphorylation is probably the most widely studied form of PTM, there are many other PTMs, including acylation, ubiquitylation, methylation, acetylation, thiolation, nitration, and glycosylation (107). The focus of this review is protein glycosylation, specifically, O-glycosylation of nuclear and cytoplasmic proteins. Classical protein glycosylation occurs in the endoplasmic reticulum and Golgi, leading to the formation of stable and complex elongated oligosaccharide structures via both N-linkage on asparagine and O-linkage on the hydroxy amino acids serine and threonine in addition to hydroxyproline, hydroxylysine, and tyrosine residues of proteins that become secreted or membrane component glycoproteins (189). In contrast, glycosylation of nuclear and cytoplasmic proteins is a rapid and dynamic modification of serine or threonine residues by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (OGlcNAc) (97,195); this process is referred to as protein O-GlcNAcylation to contrast it wi...

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

“…A shorter splice variant of O-GlcNAc-transferase has been identified that exhibits preferred mitochondrial localization (20). In diabetes, increased O-GlcNAcylation of a set of cytoplasmatic and nuclear proteins has been shown, which is likely due to the activation of the hexosamine biosynthetic pathway (18,(21)(22)(23). Consistent with these observations, we found that several mitochondrial proteins are highly O-GlcNAcylated in cardiomyocytes exposed to high glucose (18,24).…”

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

“…A cross-talk between redox and O-GlcNAcylation signaling has also been described (101). This may have a strong relevance in cardioprotection; in fact an increase in mitochondrial ROS production may be accompanied by an increase in O-GlcNAcylation (Fig.…”

“…4). It has been observed that ROS may increase flux through the hexosamine biosynthetic pathway, resulting in greater O-GlcNacylation of proteins (101,160).…”

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

“…Protein O-GlcNAcylation has been shown to be involved in numerous cellular processes including signal transduction, protein trafficking, protein-protein interactions, protein degradation, and regulation of gene expression and cell survival responses (12,72,145). Increased O-GlcNAc levels have also been implicated in contributing to the adverse effects of hyperglycemia in a wide range of tissues and cells, and sustained O-GlcNAcylation is now widely appreciated as a pathogenic mediator of diabetic complications (16,28,46,64).…”