Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation

Abstract

The nutrient sensor, O-linked N-acetylglucosamine (O-GlcNAc), cycles on and off nuclear and cytosolic proteins to regulate many cellular processes, including transcription and signaling. Dysregulated O-GlcNAcylation and its interplay with phosphorylation contribute to the etiology of diabetes, cancer, and neurodegeneration. Herein, we review recent findings about O-GlcNAc's regulation of cell physiology.

Figure 1. O-GlcNAcylation is a key link between nutrient sensing and signaling

a) The biosynthesis of UDP-GlcNAc by HBP integrates the flux through many metabolic pathways linked to nutrient intake. Variation in part or all of these pathways impacts directly the flux through HBP, the production of UDP-GlcNAc and the rate of O-GlcNAcylation. b) Schematic depicting the relationship of O-GlcNAcylation with phosphorylation for a single protein. c) Depending upon UDP-GlcNAc concentration, OGT modifies specific kinases. Regulation of substrate specificity and/or activity of upstream kinases by O-GlcNAcylation have profound effects on signaling and cellular physiology.

Figure 2. Regulation of gene transcription and epigenetics by O-GlcNAcylation

O-GlcNAc cycling on gene specific transcription factors and components of the basal transcriptional machinery regulates gene activation. Sp1 is one of the most extensively modified transcription factors. The CTD of the RNA polymerase II (RNAP II) is itself O-GlcNAcylated at the transcription initiation step. The switch from transcription initiation to elongation requires OGA activity to remove the sugar. O-GlcNAcylation or OGT interaction with master regulators of epigenetic marks also switch on and off gene expression. The complex comprised of Sin3A, HDAC and OGT has been proposed to inhibit transcription. OGT O-GlcNAcylates and/or forms complexes with TETs that drive DNA methylation. H2B O-GlcNAcylation and ubiquitination are associated with transcriptionally active loci. Insert emphasizes the role of O-GlcNAcylation in the regulation of the histone code.