Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

Abstract

O-GlcNAcylation corresponds to the addition of N-Acetylglucosamine (GlcNAc) on serine or threonine residues of cytosolic, nuclear and mitochondrial proteins. This reversible modification is catalysed by a unique couple of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT uses UDP-GlcNAc produced in the hexosamine biosynthesis pathway, to modify proteins. UDP-GlcNAc is at the cross-roads of several cellular metabolisms, including glucose, amino acids and fatty acids. Therefore, OGT is considered as a metabolic sensor that post-translationally modifies proteins according to nutrient availability. O-GlcNAcylation can modulate protein-protein interactions and regulate protein enzymatic activities, stability or subcellular localization. In addition, it can compete with phosphorylation on the same serine or threonine residues, or regulate positively or negatively the phosphorylation of adjacent residues. As such, O-GlcNAcylation is a major actor in the regulation of cell signaling and has been implicated in numerous physiological and pathological processes. A large body of evidence have indicated that increased O-GlcNAcylation participates in the deleterious effects of glucose (glucotoxicity) in metabolic diseases. However, recent studies using mice models with OGT or OGA knock-out in different tissues have shown that O-GlcNAcylation protects against various cellular stresses, and indicate that both increase and decrease in O-GlcNAcylation have deleterious effects on the regulation of energy homeostasis.

Keywords: Glucotoxicity; Inflammation; Knock-out mouse models; Metabolic diseases; O-GlcNAc transferase; O-GlcNAcase; O-GlcNAcylation; Oxidative stress.

Fig. 1

O-GlcNAc-cycling enzymes. A Three OGT isoforms, two nucleocyplasmic (ncOGT and sOGT) and one mitochondrial (mOGT), are generated by alternative splicing of the OGT messenger RNA (MTS Mitochondria Targeting Sequence). OGT comprises a N-terminal domain containing tetra-tricopeptide repeats (TPR) involved in protein–protein interactions and a C-terminal domain with glycosyltransferase activity. The PPO domain (Phophosphatidylinositol Phosphate binding domain of OGT), located in the C-terminal part, is involved in the recruitment of the OGT to the plasma membrane, allowing its interaction with insulin signaling proteins. CD1, CD2 Catalytic domains 1 and 2. ID intervening domain. B Two OGA isoforms, long (L-OGA) and short (S-OGA) are generated by alternative splicing of the OGA messenger RNA. L-OGA comprises a hexosaminidase domain in its N-terminal region and a pseudo-histone acetyltransferase domain (HAT) in its C-terminal region. S-OGA does not have the pseudo-HAT domain and seems to be addressed to the mitochondria via a 15 specific amino acids sequence located in the C-terminal region. C O-GlcNAcylation is a highly dynamic process regulated by the different OGT and OGA isoforms in different cell compartments

Fig. 2

O-GlcNAcylation depends on the energy status of the cell. The hexosamine biosynthesis pathway results in the formation of UDP-GlcNAc, which is used by OGT to O-GlcNAcylate proteins. UDP-GlcNAc is at the crossroads of different cellular metabolisms (glucose, amino acids (glutamine), fatty acids (acetyl-CoA) and nucleotides (UTP)) and therefore reflects the energy status of the cell. HK Hexokinase, GPI Glucose-6-phosphate isomerase, GFAT Glutamine-6-P amidotransferase, GNA1 Glucosamine 6-P acetyltransferase, PGM3 Phosphoacetylglucosamine mutase, UAP1 UDP-N-Acetylhexosamine pyrophosphorylase 1, OGT O-GlcNAc transferase, OGA O-GlcNAcase

Fig. 3

Lessons from OGT and OGA knock-out mice. A Tissue-specific OGT-KO mice have brought important insights into the role of O-GlcNAcylation in the regulation of energy homeostasis. B Only few tissue-specific OGA-KO mice have been developed to date, and contradictory results have been obtained for the regulation of energy homeostasis in two different models of mice with global OGA haploinsufficiency