Stress-induced O-GlcNAcylation: an adaptive process of injured cells

Abstract

In the 30 years, since the discovery of nucleocytoplasmic glycosylation, O-GlcNAc has been implicated in regulating cellular processes as diverse as protein folding, localization, degradation, activity, post-translational modifications, and interactions. The cell co-ordinates these molecular events, on thousands of cellular proteins, in concert with environmental and physiological cues to fine-tune epigenetics, transcription, translation, signal transduction, cell cycle, and metabolism. The cellular stress response is no exception: diverse forms of injury result in dynamic changes to the O-GlcNAc subproteome that promote survival. In this review, we discuss the biosynthesis of O-GlcNAc, the mechanisms by which O-GlcNAc promotes cytoprotection, and the clinical significance of these data.

Keywords: OGT; chaperone; glycoprotein; heat shock response; mgea5; signal transduction.

Figure 1.

In response to injury, there are significant and dynamic changes to the OGlcNAc sub-proteome. As increasing O-GlcNAc levels promotes survival, and as decreasing OGlcNAc levels promotes apoptosis and necrosis, stress-induced changes in O-GlcNAcylation are thought to reprogram cellular pathways promoting survival. Stress-induced changes in the OGlcNAc modification correlate with increased expression, activity and substrate targeting of OGT (yellow) and decreased expression and activity of OGA (blue), as well as increased flux through the hexosamine biosynthetic pathway. One mechanism supporting metabolic remodeling is increased expression of GFAT, the rate-limiting enzyme in the hexosamine biosynthetic pathway, which is mediated by the transcription factor Xbp1s. O-GlcNAc has been demonstrated to activate proteins/pathways (green) leading to cell survival (for example, heat shock protein expression) and to inhibit proteins (red) that promote cell death (for example, CHOP activation), collectively increasing cellular protection. For some pathways, the molecular mechanism by which O-GlcNAc mediates survival/inhibition are unknown (dashed lines), whereas for others the O-GlcNAcylated proteins and sites have been identified (solid lines). Nonetheless, additional work is required to fully delineate how O-GlcNAc promotes a pro-survival phenotype. Abbreviations used in this figure: G6PD, Glucose-6-phosphate dehydrogenase; GFAT, Glutamine fructose-6-phosphate aminotransferase; GSK3β, Glycogen synthase kinase 3β; mPTP, mitochondrial permeability transition pore; OGA, O-GlcNAcase; OGT, O-GlcNAc transferase; IL1, Interleukin 1; PFK1, Phosphofructokinase 1; TNF〈, Tumor necrosis factor 〈;Xbp1s, Spliced X-box binding protein 1.