Key Points
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O-GlcNAcylation is a nutrient- and stress-responsive post-translational modification (PTM) that involves the attachment of O-linked N-acetylglucosamine moieties to Ser and Thr residues of cytoplasmic, nuclear and mitochondrial proteins. A single pair of enzymes — O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) — controls the dynamic cycling of this PTM.
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Potential mechanisms that enable a single OGT enzyme to recognize hundreds of protein substrates include substrate-specific interactions with the tetratricopeptide repeat (TPR) domain of OGT and context-dependent recruitment of OGT to its substrates by a hierarchy of conserved adaptor proteins. Furthermore, in response to cellular stress, O-GlcNAcylation may occur nonspecifically in unstructured regions of unfolded proteins in order to block their aggregation and degradation and facilitate their refolding.
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O-GlcNAcylation is involved in the spatiotemporal regulation of diverse cellular processes, which include transcription, epigenetic modifications and cell signalling dynamics. O-GlcNAcylation is highly dynamic and often transient, but the mechanisms underlying the temporal control of O-GlcNAc signalling are largely unknown.
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Nutrient availability regulates cellular O-GlcNAcylation levels not only by determining the abundance of the donor substrate uridine diphosphate GlcNAc (UDP-GlcNAc) but also by modulating the levels of OGT, OGA and their respective adaptor proteins and substrates. Hormones such as insulin, glucagon and ghrelin are secreted in response to systemic metabolic changes and modulate O-GlcNAc signalling in specific cell types and tissues to regulate key response pathways that help maintain metabolic homeostasis.
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Cellular O-GlcNAcylation levels may be maintained within an 'optimal zone' by a 'buffering system' that is generated by mutual regulation of OGT and OGA at the transcriptional and post-translational levels. Maintenance of O-GlcNAc homeostasis is essential for optimal cellular function, and disruption of the cellular O-GlcNAcylation 'buffer' may contribute to the pathogenesis of various human diseases.
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O-GlcNAcylation can be viewed as the essential 'grease and glue' of the cell: it acts as a 'grease' by coating target proteins (folded or unfolded, mature or nascent) and preventing unwanted protein aggregation or modification; it also acts as a 'glue' by modulating protein–protein interactions in time and space in response to internal and external cues, thereby affecting the functions of various proteins in the cell.
Abstract
O-GlcNAcylation — the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins — is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes — O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) — controls the dynamic cycling of this protein modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O-GlcNAcylation at levels that range from structural and molecular biology to cell signalling and gene regulation to physiology and disease. New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.
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Change history
26 May 2017
In the version of this article initially published online, several instances of the definition of O-GlcNAcylation have been corrected. In addition, a number of formatting mistakes have been addressed. These errors have been corrected in the HTML, print and PDF versions of the article.
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Acknowledgements
The authors thank all members of the Yang laboratory for stimulating discussions. This work was supported by grants from the US National Institutes of Health (R01DK089098, R01DK102648, P01DK057751), the American Cancer Society (RSG-14-244-01-TBE), the State of Connecticut (DPH2014-0139) and the Ellison Medical Foundation to X.Y.
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Glossary
- Tetratricopeptide repeats
-
(TPRs). Thirty-four amino acid structural motifs that are found in tandem arrays in many proteins; they mediate protein–protein interactions and the assembly of protein complexes.
- Molecular dynamics simulations
-
A computational method that simulates the physical movements of atoms and molecules; it can be used to model the internal motions and conformational changes of biological macromolecules to understand the physical basis of their structures and functions.
- Orexin
-
A hypothalamic neuropeptide that regulates appetite, arousal and wakefulness; it is also known as hypocretin.
- PPARγ co-activator 1α
-
(PGC1α). A transcriptional co-activator and master regulator of gluconeogenesis and mitochondrial biogenesis.
- Gluconeogenesis
-
A metabolic pathway that produces glucose from various carbon sources that include glycerol, lactate and some amino acids; it occurs primarily in the liver and kidney in mammals.
- Pyruvate kinase isoform M2
-
(PKM2). An isozyme of pyruvate kinase, the enzyme that catalyses the final step of glycolysis; it has been implicated in the reprogramming of metabolic pathways in cancer.
- Aerobic glycolysis
-
The preferential utilization of glycolysis and lactic acid fermentation for ATP production despite the availability of oxygen for oxidative phosphorylation; it is a hallmark of metabolic reprogramming in cancer.
- Lectin
-
A protein that recognizes and binds to specific carbohydrates; these carbohydrates can be monosaccharides or oligosaccharides, and they can be soluble or attached to glycolipids and glycoproteins.
- Molecular docking simulations
-
A computational method that simulates the process of a ligand binding to an enzyme or receptor; it can be used to predict the preferred orientation of a ligand in the active site of an enzyme.
- Transactivation
-
The increased expression of a gene that is induced by the expression of a transactivator protein (for example, a transcription factor); transcription factors possess transactivation domains that contain binding sites for transcriptional co-regulators.
- Transrepression
-
The repression of the activity of one protein (for example, a transcription factor) through its interaction with a second protein.
- Pre-initiation complex
-
A large protein assembly that performs various functions that are required for transcription initiation (for example, the recruitment of RNA polymerase II to transcription start sites and the unwinding of DNA to allow for RNA polymerase II binding).
- Lipid rafts
-
Cholesterol- and sphingolipid-enriched microdomains in the plasma membrane, which serve as organizing centres for signal transduction.
- Ketogenesis
-
The production of ketone bodies (acetoacetate, acetone and β-hydroxybutyrate) from the catabolism of fatty acids and some amino acids; ketone bodies become a major energy source for various organs during fasting and for the brain during long-term starvation.
- Browning of white adipose tissue
-
The increased white adipose tissue expression of uncoupling protein 1 (UCP1), which is typically found in the mitochondria of brown adipose tissue; UCP1 uncouples the electron transport chain from ATP production to generate heat.
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Yang, X., Qian, K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18, 452–465 (2017). https://doi.org/10.1038/nrm.2017.22
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DOI: https://doi.org/10.1038/nrm.2017.22
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