Nutrient-driven O-GlcNAc cycling - think globally but act locally

Journal of Cell Science (Impact Factor: 5.43). 04/2014; 127(9). DOI: 10.1242/jcs.113233
Source: PubMed


Proper cellular functioning requires that cellular machinery behave in a spatiotemporally regulated manner in response to global changes in nutrient availability. Mounting evidence suggests that one way this is achieved is through the establishment of physically defined gradients of O-GlcNAcylation (O-linked addition of N-acetylglucosamine to serine and threonine residues) and O-GlcNAc turnover. Because O-GlcNAcylation levels are dependent on the nutrient-responsive hexosamine signaling pathway, this modification is uniquely poised to inform upon the nutritive state of an organism. The enzymes responsible for O-GlcNAc addition and removal are encoded by a single pair of genes: both the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA, also known as MGEA5) genes are alternatively spliced, producing protein variants that are targeted to discrete cellular locations where they must selectively recognize hundreds of protein substrates. Recent reports suggest that in addition to their catalytic functions, OGT and OGA use their multifunctional domains to anchor O-GlcNAc cycling to discrete intracellular sites, thus allowing them to establish gradients of deacetylase, kinase and phosphatase signaling activities. The localized signaling gradients established by targeted O-GlcNAc cycling influence many important cellular processes, including lipid droplet remodeling, mitochondrial functioning, epigenetic control of gene expression and proteostasis. As such, the tethering of the enzymes of O-GlcNAc cycling appears to play a role in ensuring proper spatiotemporal responses to global alterations in nutrient supply.

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    • "Since then, proteins involved at each level of transcriptional regulation, including factors regulating DNA methylation, chromatin accessibility, and modification , have been found to be O-GlcNAc modified. There has been a wave of recent reviews that summarize the vast amount of studies that have explored possible mechanisms of how Ogt regulates transcription (e.g., Ozcan et al. 2010; Hanover et al. 2012; Lewis 2013; Gut and Verdin 2013; Vaidyanathan et al. 2014; Jóźwiak et al. 2014; Forma et al. 2014; Dehennaut et al. 2014; Lewis and Hanover 2014; Harwood and Hanover 2014). Here, we critically assess the methodologies and original evidence that served as basis for establishing current views on how O-GlcNAcylation might impart on transcription. "
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    ABSTRACT: O-linked β-N-Acetylglucosamine (O-GlcNAc) is a posttranslational modification that is catalyzed by O-GlcNAc transferase (Ogt) and found on a plethora of nuclear and cytosolic proteins in animals and plants. Studies in different model organisms revealed that while O-GlcNAc is required for selected processes in Caenorhabditis elegans and Drosophila, it has evolved to become required for cell viability in mice, and this has challenged investigations to identify cellular functions that critically require this modification in mammals. Nevertheless, a principal cellular process that engages O-GlcNAcylation in all of these species is the regulation of gene transcription. Here, we revisit several of the primary experimental observations that led to current models of how O-GlcNAcylation affects gene expression. In particular, we discuss the role of the stable association of Ogt with the transcription factors Hcf1 and Tet, the two main Ogt-interacting proteins in nuclei of mammalian cells. We also critically evaluate the evidence that specific residues on core histones, including serine 112 of histone 2B (H2B-S112), are O-GlcNAcylated in vivo and discuss possible physiological effects of these modifications. Finally, we review our understanding of the role of O-GlcNAcylation in Drosophila, where recent studies suggest that the developmental defects in Ogt mutants are all caused by lack of O-GlcNAcylation of a single transcriptional regulator, the Polycomb repressor protein Polyhomeotic (Ph). Collectively, this reexamination of the experimental evidence suggests that a number of recently propagated models about the role of O-GlcNAcylation in transcriptional control should be treated cautiously.
    Chromosoma 04/2015; DOI:10.1007/s00412-015-0513-1 · 4.60 Impact Factor
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    ABSTRACT: O-GlcNAcylation has emerged as a critical post-translational modification important for a wide array of cellular processes. This modification has been identified on a large pool of intracellular proteins that have wide-ranging roles, including transcriptional regulation, cell cycle progression, and signaling, among others. Interestingly, in mammals the single gene encoding O-GlcNAc Transferase (OGT) is located on the X-chromosome near the Xist locus suggesting that tight dosage regulation is necessary for normal development. Herein, we highlight the importance of OGT dosage and consider how its genomic location can contribute to a gender-specific increased risk for a number of diseases.
    Biochemical and Biophysical Research Communications 06/2014; 453(2). DOI:10.1016/j.bbrc.2014.06.068 · 2.30 Impact Factor
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    ABSTRACT: O-GlcNAc transferase is an essential mammalian enzyme responsible for transferring a single GlcNAc moiety from UDP-GlcNAc to specific serine/threonine residues of hundreds of nuclear and cytoplasmic proteins. This modification is dynamic and has been implicated in numerous signaling pathways. An unexpected second function for O-GlcNAc transferase as a protease involved in cleaving the epigenetic regulator HCF-1 has also been reported. Recent structural and biochemical studies that provide insight into the mechanism of glycosylation and HCF-1 cleavage will be described, with outstanding questions highlighted.
    Journal of Biological Chemistry 10/2014; 289(50). DOI:10.1074/jbc.R114.604405 · 4.57 Impact Factor
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