Decreased O-Linked GlcNAcylation Protects from Cytotoxicity Mediated by Huntingtin Exon1 Protein Fragment

Kumar, Amit; Singh, Pankaj Kumar; Parihar, Rashmi; Dwivedi, Vibha; Lakhotia, S. C.; Ganesh, Subramaniam

doi:10.1074/jbc.m114.553321

Cited by 57 publications

(54 citation statements)

References 53 publications

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“…of the unfolded protein response, and endoplasmic reticulum stress (59), decreased proteasomal degradation (60), or blunted cellular autophagy (61,62). Although mechanistically reasonable, further studies are needed to determine the process by which HGϩGNS increases chronic insulin secretion and protein levels.…”

Section: Discussionmentioning

confidence: 99%

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Durning

Flanagan-Steet

Prasad

et al. 2016

Journal of Biological Chemistry

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The post-translational protein modification O-linked ␤-Nacetylglucosamine (O-GlcNAc) is a proposed nutrient sensor that has been shown to regulate multiple biological pathways. This dynamic and inducible enzymatic modification to intracellular proteins utilizes the end product of the nutrient sensing hexosamine biosynthetic pathway, UDP-GlcNAc, as its substrate donor. Type II diabetic patients have elevated O-GlcNAc-modified proteins within pancreatic beta cells due to chronic hyperglycemia-induced glucose overload, but a molecular role for O-GlcNAc within beta cells remains unclear. Using directed pharmacological approaches in the mouse insulinoma-6 (Min6) cell line, we demonstrate that elevating nuclear O-GlcNAc increases intracellular insulin levels and preserves glucose-stimulated insulin secretion during chronic hyperglycemia. The molecular mechanism for these observed changes appears to be, at least in part, due to elevated O-GlcNAcdependent increases in Ins1 and Ins2 mRNA levels via elevations in histone H3 transcriptional activation marks. Furthermore, RNA deep sequencing reveals that this mechanism of altered gene transcription is restricted and that the majority of genes regulated by elevated O-GlcNAc levels are similarly regulated by a shift from euglycemic to hyperglycemic conditions. These findings implicate the O-GlcNAc modification as a potential mechanism for hyperglycemic-regulated gene expression in the beta cell.

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Section: Discussionmentioning

confidence: 99%

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Durning

Flanagan-Steet

Prasad

et al. 2016

Journal of Biological Chemistry

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“…In contrast, it has recently been shown that suppression of O-GlcNAcylation by overexpression of OGA led to decreased p62 and increased LC3-II, suggesting an enhanced autophagic flux. Azaserine inhibits glutamine fructose-6-phosphate amidotransferase, one of the key enzymes of hexosamine biosynthesis pathway, and thereby leads to decreased O-GlcNAcylation and a decrease of LC3-II and p62 in Neuro2A cells, attenuating toxicity by mutant HUNTINGIN exon 1 fragment in these cells (71). …”

Section: Regulation Of Autophagy By O-glcnacylationmentioning

confidence: 99%

Regulation of autophagy by protein post-translational modification

Wani

Boyer-Guittaut

Dodson

et al. 2015

Laboratory Investigation

136

116

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Autophagy is a lysosomal mediated intracellular protein degradation process that involves ~38 autophagy related genes as well as key signaling pathways that sense cellular metabolic and redox status, and plays an important role in quality control of macromolecules and organelles. As with other major cellular pathways, autophagy proteins are subject to regulatory post-translational modification. Phosphorylation is so far the most intensively studied post-translational modification in the autophagy process, followed by ubiquitination and acetylation. An interesting and new area is also now emerging, which appears to complement these more traditional mechanisms, and includes O-GlcNAcylation and redox regulation at thiol residues. Identification of the full spectrum of post-translational modifications of autophagy proteins, and determination of their impact on autophagy will be crucial for a better understanding of autophagy regulation, its deficits in diseases, and how to exploit this process for disease therapies.

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“…In C. elegans , mutations in O-GlcNAc cycling enzymes resulted in elevated levels of GFP::LGG-1 (homolog of Atg8 and LC3) upon starvation [87, 88]. In contrast to observations in tauopathy models, O-GlcNAcylation plays a detrimental role against mutant huntingtin toxicity in cells and fly models, as demonstrated by either overexpression of OGT or OGA, or by pharmacological alterations of O-GlcNAc levels using azaserine or glucosamine [89]. Decreasing O-GlcNAcylation enhances the fusion of autophagosomes with lysosomes, thereby elevating autophagic flux.…”

Section: O-glcnacylation Apoptosis and Autophagymentioning

confidence: 99%

“…Decreasing O-GlcNAcylation enhances the fusion of autophagosomes with lysosomes, thereby elevating autophagic flux. This is associated with decreased mHtt aggregates in flies (Fig.5A) [89]. Autophagy inhibition may be mediated by O-GlcNAcylation of the SNARE protein SNAP29, inhibiting autophagosome-lysosome fusion and autophagic flux [90].…”

Section: O-glcnacylation Apoptosis and Autophagymentioning

confidence: 99%

O-GlcNAcylation and neurodegeneration

Wani

Chatham

Darley‐Usmar

et al. 2017

Brain Research Bulletin

102

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O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of β-D-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins. The two enzymes responsible for O-GlcNAc cycling are O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA); their expression and activities in brain are age dependent. More than 1000 O-GlcNAc protein targets have been identified which play critical roles in many cellular processes. In mammalian brain, O-GlcNAc modification of Tau decreases its phosphorylation and toxicity, suggesting a neuroprotective role of pharmacological elevation of brain O-GlcNAc for Alzheimer’s disease treatment. Other observations suggest that elevating O-GlcNAc levels may decrease protein clearance or induce apoptosis. This review highlights some of the key findings regarding O-GlcNAcylation in models of neurodegenerative diseases.

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Decreased O-Linked GlcNAcylation Protects from Cytotoxicity Mediated by Huntingtin Exon1 Protein Fragment

Cited by 57 publications

References 53 publications

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Regulation of autophagy by protein post-translational modification

O-GlcNAcylation and neurodegeneration

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