Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system - PubMed (original) (raw)

Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Boglarka Laczy et al. Am J Physiol Heart Circ Physiol. 2009 Jan.

Abstract

The posttranslational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide beta-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.

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Figures

Fig. 1.

Fig. 1.

The hexosamine biosynthesis pathway (HBP) and protein _O_-GlcNAcylation. Glucose imported into cells is rapidly phosphorylated to glucose-6-phosphate (glucose-6-P) and converted to fructose-6-phosphate (fructose-6-P), which is metabolized to glucosamine-6-phosphate by

l

-glutamine-

d

-fructose 6-phosphate amidotransferase (GFAT), resulting in the synthesis of UDP-_N_-acetylglucosamine (UDP-GlcNAc). GFAT can be inhibited by the glutamine analogs 6-diazo-5-oxo-

l

-norleucine (DON) and _O_-diazoacetyl-

l

-serine (azaserine). Flux through the HBP can be increased with glucosamine, which bypasses GFAT. UDP-GlcNAc is a sugar donor for classical glycosylation reactions in the endoplasmic reticulum (ER) and Golgi apparatus and is also the obligatory substrate for uridine-diphospho-_N_-acetylglucosamine:polypeptide β-_N_-acetylglucosaminyltransferase (OGT), leading to the formation of _O_-linked β-_N_-acetylglucosamine (_O_-GlcNAc)-modified proteins. β-_N_-acetylglucosaminidase (_O_-GlcNAcase) catalyzes the removal of _O_-GlcNAc from proteins. The level of _O_-GlcNAc on proteins can be blocked by inhibiting OGT with the uridine analog alloxan or with 2[(4-chlorophenyl)imino]tetrahydro-4-oxo-3-[2-tricyclo(3.3.1.13.7)dec-1-ylethel] (TTO4), whereas _O_-GlcNAcylation of proteins can be rapidly increased by inhibiting _O_-GlcNAcase with _O_-(2-acetamido-2-deoxy-

d

-glucopyranosylidene)amino-_N_-phenylcarbamate (PUGNAc) or with 1,2 dideoxy-2-methyl-

d

-glucopyranoso(2,1-

d

)-2-thiazoline (NAG-thiazoline). S/T, serine/threonine.

Fig. 2.

Fig. 2.

The interaction between _O_-GlcNAcylation and _O_-phosphorylation. Analogous to phosphorylation, _O_-GlcNAcylation is a dynamic posttranslational modification occurring on serine/threonine residues of proteins. For a subset of cellular proteins, there is a competitive relationship between _O_-GlcNAc and _O_-phosphate for the same serine/threonine residues, although there can be adjacent or multiple occupancy for phosphorylation and _O_-GlcNAcylation on the same protein. The combination of _O_-phosphate and _O_-GlcNAc modifications creates molecular diversity by altering specific protein sites that are involved in signaling events. Thus, this complex interplay between phosphorylation and _O_-GlcNAcylation can dynamically regulate protein functions and modulate critical signaling pathways. OGA, β-_N_-acetylglucosaminidase. [Modified from Zachara and Hart (226).]

Fig. 3.

Fig. 3.

Relationship between mitochondrial oxidative stress and _O_-GlcNAcylation. Increased production of mitochondrial ROS induced either by inflammatory mediators, hyperglycemic condition (e.g., diabetic milieu), or oxidant stress leads to an increase in _O_-GlcNAc levels. Increased _O_-GlcNAcylation of mitochondrial proteins (e.g., the voltage-dependent anion channel) in turn protects cells against lethal damage by increasing mitochondrial stability and tolerance in response to oxidative stress stimuli.

Fig. 4.

Fig. 4.

Cross-talk between _O_-GlcNAc, phosphorylation, and redox signaling. A: phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) at Ser1177 results in increased eNOS activity and NO production, whereas _O_-GlcNAcylation of the same site leads to decreased enzyme activity and NO production. B: theoretically, _O_-GlcNAc-dependent reactions are not limited to interactions with specific proteins but rather act to regulate an entire pathway. For example, _O_-GlcNAc modification of eNOS decreases its activity and NO production. At the same site, Akt-mediated phosphorylation and activation of eNOS leads to increased NO-production. However, Akt is also subject to _O_-GlcNAcylation, which reduces its activity, thereby inhibiting eNOS phosphorylation and NO production.

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