A
            <i>Caenorhabditis elegans</i>
            model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout

Hanover, John A.; Forsythe, Michele E.; Hennessey, Patrick; Brodigan, Thomas M.; Love, Dona C.; Ashwell, Gilbert; Krause, Michael

doi:10.1073/pnas.0408771102

Cited by 205 publications

(285 citation statements)

References 69 publications

Supporting

Mentioning

271

Contrasting

Unclassified

Order By: Relevance

“…OGT is essential for embryonic stem cell viability and somatic cell function (O'Donnell et al 2004;Shafi et al 2000). Deletion of OGT in Arabidopsis (Jacobsen et al 1996), Drosophila (Sinclair et al 2009;Gambetta et al 2009), and mice is lethal (Shafi et al 2000), and leads to dauer phenotypes in Caenorhabditis elegans (Hanover et al 2005), suggesting that O-GlcNAc is essential for cellular homeostasis.…”

Section: O-glcnac Transferasementioning

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

120

112

View full text Add to dashboard Cite

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.

show abstract

Section: O-glcnac Transferasementioning

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

120

112

View full text Add to dashboard Cite

show abstract

“…Overexpression of OGA induces a mitotic exit phenotype (46), suggesting that it too may perform essential functions. We originally identified C. elegans OGT (25) and have shown that knockouts of ogt-1 in the nematode, although viable and fertile, have effects on insulin-like signaling (25,26). Because of the linkage of the human OGA to insulin resistance, we have now examined the impact of a knockout of the C. elegans OGA gene, oga-1.…”

mentioning

confidence: 99%

“…The pathway is highly conserved in plants and animals and plays a key signaling function in Arabidopsis, where it impacts numerous pathways, including gibberellin signaling (18)(19)(20)(21)(22)(23)(24). We recently showed that the hexosamine-signaling pathway influences insulin-like signaling in C. elegans (25,26) and mice (17). In man, the hexosamine-signaling pathway has been implicated in both diabetes mellitus and neurodegeneration (1,2,17,27).…”

mentioning

confidence: 99%

“…Levels of O-GlcNAc in oga-1(ok1207) animals were compared with WT and with ogt-1(ok430), encoding OGT-1⌬ (Fig. 1D) (26). The levels of O-GlcNAc on nuclear pore proteins were assessed by immunofluorescence by using the O-GlcNAcspecific RL2 antibody ( Fig.…”

mentioning

confidence: 99%

“…A positive control (data not shown in the graph) human OGA was found to release 120, 70, and 27 pmol of GlcNAc per min at 37°C, 25°C, and 16°C, respectively. (D) The ogt-1(ok430) deletion allele generates a truncated protein of 465 aa (OGT-1⌬) that lacks catalytic activity, as described (26). The levels of O-GlcNAc in each strain were quantified by immunoblotting by using a fluorescence-based detector as described in Materials and Methods.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Forsythe

Love²,

Lazarus³

et al. 2006

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

Self Cite

147

206

View full text Add to dashboard Cite

A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven ''hexosamine-signaling pathway.'' A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates OGlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser-and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3␤ (GSK-3␤) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C. elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling ''finetune'' insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C. elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.hexosamine ͉ insulin signaling ͉ nutrients ͉ obesity O -linked N-acetylglucosamine (O-GlcNAc) is a dynamic modification of nuclear pore complexes, transcription complexes, and kinases (1-4). Because of the diverse targets modified by O-GlcNAc, deciphering its role in cell physiology has proven challenging. Two enzymes regulate the cycling of O-GlcNAc: the O-linked GlcNAc transferase (OGT) and the glycosidase, OGlcNAcase (OGA) (1-4). In mammals, the two enzymes of OGlcNAc cycling are products of single genes; alternative splicing produces isoforms differing in subcellular location and substrate specificity (1,(5)(6)(7)(8)(9). The O-GlcNAc cycling enzymes act like kinases and phosphatases to modify Ser and Thr residues of target proteins. In addition, the hexosamine biosynthetic pathway giving rise to the O-GlcNAc donor, UDP-GlcNAc, is highly regulated and responsive to nutrient availability (4,(10)(11)(12)(13)(14).OGA, originally identified as a meningioma auto antigen and termed MGEA5 (8), is a member of the family 84 glycoside hydrolase {Carbohydrate-Active Enzymes [CAZy] database [GH 84 (caz, a)]}. OGA is highly conserved in eukaryotic evolution from Drosophila melanogaster and Caenorhabditis elegans to rodents and man. In mammals, the MGEA5 gene produces at least two isoforms differing ...

show abstract

T cell development and the physiological role of O‐GlcNAc

Abramowitz

Hanover

2018

FEBS Letters

Self Cite

View full text Add to dashboard Cite

O-GlcNAcylation is an essential post-translational modification important for integrating metabolism with cell physiology. Using diverse model systems, studies of this evolutionarily conserved intracellular glycosylation have highlighted its role in stem cell maintenance, lineage specification, and disease. Although discovered over 30 years ago, the study of O-GlcNAc continues to evolve and uncover surprising roles for O-GlcNAc and the enzymes of O-GlcNAc cycling: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In this review, using the immune system as a model of stem cell biology and cell fate determination, we discuss how O-GlcNAc is at the nexus of metabolism, proliferation, and disease.

show abstract

A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout

Cited by 205 publications

References 69 publications

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

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

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

T cell development and the physiological role of O‐GlcNAc

Contact Info

Product

Resources

About