Caenorhabditis elegans
 ortholog of a diabetes susceptibility locus:
 oga-1
 (
 O
 -GlcNAcase) knockout impacts
 O
 -GlcNAc cycling, metabolism, and dauer

Forsythe, Michele E.; Love, Dona C.; Lazarus, Brooke D.; Kim, Sang Hyun; Prinz, William A.; Ashwell, Gilbert; Krause, Michael; Hanover, John A.

doi:10.1073/pnas.0601931103

Cited by 146 publications

(222 citation statements)

References 81 publications

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“…Bioinformatic examination of the O-GlcNAc marked genes revealed a significant enrichment for genes involved in hexosamine synthesis, phosphoinositol signaling, lipid and carbohydrate metabolism, and chromatin remodeling. These observed enrichments are consistent with a number of the proposed biological functions of the O-GlcNAc modification (11,18,19,28,(37)(38)(39)(40). The predictive ability of the O-GlcNAc ChIP-on-chip data set suggests that these data can be mined to identify new O-GlcNAc-responsive pathways.…”

Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andsupporting

confidence: 59%

“…The oga-1 mutant strain also is a catalytically null allele and exhibits elevated levels of O-GlcNAc-modified proteins. These strains have been characterized previously (18,19). The normalized peak intensities across each of the Caenorhabditis elegans linkage groups is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…elegans (18,19), allowing a global analysis of the consequences of altered O-GlcNAc cycling on chromatin structure and gene expression in a living organism. Here, using whole-genome chromatin immunoprecipitation (ChIP)-on-chip tiling arrays, and transcriptional profiling, we have identified global changes in gene expression associated with defects in O-GlcNAc addition and removal.…”

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confidence: 99%

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Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Love

Ghosh

Mondoux

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

164

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Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in C. elegans . Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans , including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration.

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Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Love

Ghosh

Mondoux

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

164

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“…Modulation of OGT using small interfering RNAs is complicated by the long half-life of the protein and often produces only partial knockdown of OGT 92 . Although deletion of OGA in Caenorhabditis elegans leads to metabolic changes and increased dauer formation 93 , no mammalian knockout of OGA has yet been reported. These features have challenged efforts to study O-GlcNAc glycosylation and have limited the use of conventional genetic tools to elucidate its role in cellular processes.…”

Section: Small-molecule Inhibitors Of Ogt and Ogamentioning

confidence: 99%

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

2008

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O -GlcNAc glycosylation is a unique, dynamic form of glycosylation found on intracellular proteins of all multicellular organisms. Studies suggest that O-GlcNAc represents a key regulatory modification in the brain, contributing to transcriptional regulation, neuronal communication and neurodegenerative disease. Recently, several new chemical tools have been developed to detect and study the modification, including chemoenzymatic tagging methods, quantitative proteomics strategies and small-molecule inhibitors of O-GlcNAc enzymes. Here we highlight some of the emerging roles for O-GlcNAc in the nervous system and describe how chemical tools have significantly advanced our understanding of the scope, functional significance and cellular dynamics of this modification.O-GlcNAc glycosylation, the covalent attachment of β-N-acetylglucosamine to serine or threonine residues of proteins, is an unusual form of protein glycosylation 1 (Fig. 1). Unlike other types of glycosylation, this single-sugar modification occurs on intracellular proteins and is not elaborated further into complex glycans. The O-GlcNAc transferase (OGT) enzyme is a soluble protein that is found in the cytosol, nucleus and mitochondria 2 , rather than in the endoplasmic reticulum or Golgi. The dynamics of O-GlcNAc are also unique among sugar modifications, being cycled on a shorter time scale than protein turnover 3 . Thus, in many respects O-GlcNAc is more akin to phosphorylation than to conventional forms of glycosylation. Several reviews have described the roles of O-GlcNAc in cellular processes, such as transcription 2,4 , the stress response 5,6 , apoptosis 7,8 , signal transduction 2,9 , glucose sensing 5,10 and proteasomal degradation 5 . Only a few reviews have highlighted the importance of O-GlcNAc glycosylation in the nervous system, and those reports have focused on its potential impact on neurodegenerative diseases 11,12 . However, several lines of evidence suggest that O-GlcNAc has crucial roles in both neuronal function and dysfunction. The enzymes responsible for the modification are most highly expressed in the brain 13,14 and are enriched at neuronal synapses 15,16 . Neuron-specific deletion of the OGT gene in mice leads to abnormal development and locomotor defects, resulting in neonatal death 17 . The O-GlcNAc modification is abundant in the brain and present on many proteins important for transcription, neuronal signaling and synaptic plasticity, such as cAMPresponsive element binding protein (CREB) 18 , synaptic Ras GTPase-activating protein (synGAP) 19 and β-amyloid precursor protein (APP) 20 . An intriguing interplay between OGlcNAc glycosylation and phosphorylation has been observed in cerebellar neurons, wherein activation of certain kinase pathways reduces O-GlcNAc levels on cytoskeleton-

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“…1). Highlighting the importance of O-GlcNAc in cellular homeostasis, deletion of OGT, OGlcNAcase, and other key enzymes in the hexosamine biosynthetic pathway (HBP) is lethal in mammals (Mio et al 1999;Greig et al 2007;Boehmelt et al 2000a, b;Shafi et al 2000;Forsythe et al 2006;Yang et al 2012).…”

mentioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

116

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Cited by 146 publications

References 81 publications

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

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