Integration of O-GlcNAc into Stress Response Pathways

Abstract

The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational modification of mammalian proteins. O-GlcNAc is cycled on and off over 5000 proteins in response to diverse stimuli impacting protein function and, in turn, epigenetics and transcription, translation and proteostasis, metabolism, cell structure, and signal transduction. Environmental and physiological injury lead to complex changes in O-GlcNAcylation that impact cell and tissue survival in models of heat shock, osmotic stress, oxidative stress, and hypoxia/reoxygenation injury, as well as ischemic reperfusion injury. Numerous mechanisms that appear to underpin O-GlcNAc-mediated survival include changes in chaperone levels, impacts on the unfolded protein response and integrated stress response, improvements in mitochondrial function, and reduced protein aggregation. Here, we discuss the points at which O-GlcNAc is integrated into the cellular stress response, focusing on the roles it plays in the cardiovascular system and in neurodegeneration.

Keywords: O-GlcNAc; chaperone; glycosylation; stress.

Figure 1

O-GlcNAc cycling. O-GlcNAc is cycled on and off proteins by two enzymes: The O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), that catalyze the addition and removal of O-GlcNAc, respectively. OGT uses the nucleotide sugar UDP-GlcNAc, which is synthesized by the hexosamine biosynthetic pathways (boxed). Commercially available inhibitors of OGT and OGA are highlighted. Adapted from [1].

Figure 2

Mechanisms of Protection and Pathogenesis. Dynamic cycling of O-GlcNAc plays numerous roles in regulating cellular homeostasis and the response to cellular injury (blue). In contrast, chronic elevation or depletion of O-GlcNAc resulting in aberrant O-GlcNAc cycling is associated with disease pathogenesis (grey), including cardiomyopathy. Proteins whose function is potentiated by O-GlcNAc are highlighted in green, whereas those whose function is inhibited are highlighted in red. Glycoproteins impacted by O-GlcNAc through ill-defined mechanisms are identified in black. Abbreviations used in this figure: AKT: Protein kinase B; CaMKII: Calcium/calmodulin-dependent protein kinase II; E-C: Excitation-contraction; eIF2α: Eukaryotic translation initiation factor 2-Alpha; eIF4G1: Eukaryotic translation initiation factor 4 Gamma, 1; ER: Endoplasmic reticulum; G6PD: Glucose-6-phosphate dehydrogenase; Gata4: GATA binding protein 4; GSK3β—Glycogen Synthase Kinase β; HSP: Heat shock protein; IKK: I-kappa B kinase complex; ISR, Integrated Stress Response; mPTP: Mitochondrial permeability transition pore; NF-κB: Nuclear factor kappa B subunit 1; NFAT: Nuclear factor of activated T cells; O-GlcNAc: O-linked b N-acetylglucosamine; OGA: O-GlcNAcase; OGT: O-GlcNAc transferase PERK: PKR-like ER kinase; PFK1: Phosphofructokinase 1; PGC1α: Peroxisome Proliferative Activated Receptor, Gamma, Coactivator 1, Alpha; PGK1: Phosphoglycerate kinase 1; PI3K: Phosphatidylinositol-3-kinase; PKA: cAMP-dependent protein kinase; PKM2: Pyruvate kinase splice isoform 2; PPP, Pentose Phosphate Pathway; Rac1: Ras-related C3 botulinum toxin substrate 1; RIPK: Receptor-interacting serine/threonine kinase; ROS: Reactive oxygen species; SERCA2A: Sarcoplasmic/endoplasmic reticulum calcium ATPase 2; TAB1: TAK1-binding protein 1; TDP43: Transactive response DNA binding protein 43; ULK1: Unc-51 like autophagy activating kinase 1; VDAC: Voltage dependent anion channel.