Protein O -GlcNAcylation: emerging mechanisms and functions

Key Points 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. 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. 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. 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. 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. 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.