Oxidative stress induces transient O‐Glc<scp>NA</scp>c elevation and tau dephosphorylation in <scp>SH</scp>‐<scp>SY</scp>5Y cells

Kátai, Emese; Pál, József; Poór, Viktor Soma; Purewal, Rupeena; Miseta, Attila; Nagy, Tamás

doi:10.1111/jcmm.12910

Cited by 30 publications

(19 citation statements)

References 43 publications

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“…Our results argue instead that the direct target of iron is the O-GlcNAc pathway. Iron is a known oxidant, but nonspecific oxidant stress is probably not the mediator of the results presented herein insofar as oxidant stress, in general, increases levels of O-GlcNAcylation (36). Iron did not affect mRNA or protein levels of OGA, and the fact that iron exerts its full effect in mice with deletion of the OGA gene in adipocytes demonstrates that the decreased glycosylation is not due to increased OGA activity.…”

Section: Figure 4 Effect Of Iron On O-glycosylation Of Creb Occupanmentioning

confidence: 56%

Iron down-regulates leptin by suppressing protein O-GlcNAc modification in adipocytes, resulting in decreased levels of O-glycosylated CREB

Gao

Liu

Bai

et al. 2019

Journal of Biological Chemistry

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We previously reported that iron down-regulates transcription of the leptin gene by increasing occupancy of phosphorylated cAMP response element-binding protein (pCREB) at two sites in the leptin gene promoter. Several nutrient-sensing pathways including O-GlcNAcylation also regulate leptin. We therefore investigated whether O-glycosylation plays a role in ironand CREB-mediated regulation of leptin. We found that high iron decreases protein O-GlcNAcylation both in cultured 3T3-L1 adipocytes and in mice fed high-iron diets and downregulates leptin mRNA and protein levels. Glucosamine treatment, which bypasses the rate-limiting step in the synthesis of substrate for glycosylation, increased both O-GlcNAc and leptin, whereas inhibition of O-glycosyltransferase (OGT) decreased O-GlcNAc and leptin. The increased leptin levels induced by glucosamine were susceptible to the inhibition by iron, but in the case of OGT inhibition, iron did not further decrease leptin. Mice with deletion of the O-GlcNAcase gene, either via whole-body heterozygous deletion or through adipocyte-targeted homozygous deletion, exhibited increased O-GlcNAc levels in adipose tissue and increased leptin levels that were inhibited by iron. Of note, iron increased the occupancy of pCREB and decreased the occupancy of O-GlcNAcylated CREB on the leptin promoter. These patterns observed in our experimental models suggest that iron exerts its effects on leptin by decreasing O-glycosylation and not by increasing protein deglycosylation and that neither O-GlcNAcase nor OGT mRNA and protein levels are affected by iron. We conclude that iron down-regulates leptin by decreasing CREB glycosylation, resulting in increased CREB phosphorylation and leptin promoter occupancy by pCREB.

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Section: Figure 4 Effect Of Iron On O-glycosylation Of Creb Occupanmentioning

confidence: 56%

Iron down-regulates leptin by suppressing protein O-GlcNAc modification in adipocytes, resulting in decreased levels of O-glycosylated CREB

Gao

Liu

Bai

et al. 2019

Journal of Biological Chemistry

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“…Oxidative stress induced by treatment with H 2 O 2 in SH‐SY5Y cells showed a high level of total O‐GlcNAcylation. The reciprocal relationship between phosphorylation and glycosylation under oxidative stress indicates the possible role of interplay between oxidative stress and glycosylation in AD pathology . Glycosylation and phosphorylation of tau are regulated with respect to each other in a complex manner.…”

Section: Glycosylationmentioning

confidence: 99%

Role of Post‐translational Modifications in Alzheimer's Disease

2020

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The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug‐discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post‐translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in‐depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease‐relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug‐discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.

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“…This paradox may be resolved if O-GlcNAc is considered as a stress adaptation mechanism that is triggered by acute challenges, such as hypoglycemia. Indeed, a large number of data suggest that protein O-GlcNAc modification dynamically increases after the cells are exposed to various type of environmental challenges [ 15 , 16 ].…”

Section: Regulation Of Proteins By O-glcnacmentioning

confidence: 99%

“…It also seems to be that stress response and O-GlcNAc are connected [ 14 , 55 ]. Increasing number of evidences suggest that oxidative stress may stimulate the hexosamine biosynthetic pathway and consequently O-GlcNAcylation [ 16 , 51 ]. Reactive oxygen species (ROS) can modify protein functions by oxidation of cysteine residues [ 56 ].…”

Section: Oxidative Stress and O-glcnacmentioning

confidence: 99%

“…In these cells, urea induced ROS production which increased O-GlcNAc modification of insulin signaling molecule IRS-1 [ 60 ]. Kátai et al demonstrated that protein O-GlcNAcylation was transiently elevated in a neuroblastoma cell line following oxidative stress [ 16 ]. The expressional level or the activity of OGT after various stresses, including hypoxia/reperfusion and oxidative stress, has been also found to be increased [ 15 , 16 , 61 ].…”

Section: Oxidative Stress and O-glcnacmentioning

confidence: 99%

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The Role of Stress‐Induced O‐GlcNAc Protein Modification in the Regulation of Membrane Transport

Fisi

Miseta

Nagy

2017

Oxidative Medicine and Cellular Longevity

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O-linked N-acetylglucosamine (O-GlcNAc) is a posttranslational modification that is increasingly recognized as a signal transduction mechanism. Unlike other glycans, O-GlcNAc is a highly dynamic and reversible process that involves the addition and removal of a single N-acetylglucosamine molecule to Ser/Thr residues of proteins. UDP-GlcNAc—the direct substrate for O-GlcNAc modification—is controlled by the rate of cellular metabolism, and thus O-GlcNAc is dependent on substrate availability. Serving as a feedback mechanism, O-GlcNAc influences the regulation of insulin signaling and glucose transport. Besides nutrient sensing, O-GlcNAc was also implicated in the regulation of various physiological and pathophysiological processes. Due to improvements of mass spectrometry techniques, more than one thousand proteins were detected to carry the O-GlcNAc moiety; many of them are known to participate in the regulation of metabolites, ions, or protein transport across biological membranes. Recent studies also indicated that O-GlcNAc is involved in stress adaptation; overwhelming evidences suggest that O-GlcNAc levels increase upon stress. O-GlcNAc elevation is generally considered to be beneficial during stress, although the exact nature of its protective effect is not understood. In this review, we summarize the current data regarding the oxidative stress-related changes of O-GlcNAc levels and discuss the implications related to membrane trafficking.

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Oxidative stress induces transient O‐GlcNAc elevation and tau dephosphorylation in SH‐SY5Y cells

Cited by 30 publications

References 43 publications

Iron down-regulates leptin by suppressing protein O-GlcNAc modification in adipocytes, resulting in decreased levels of O-glycosylated CREB

Iron down-regulates leptin by suppressing protein O-GlcNAc modification in adipocytes, resulting in decreased levels of O-glycosylated CREB

Role of Post‐translational Modifications in Alzheimer's Disease

The Role of Stress‐Induced O‐GlcNAc Protein Modification in the Regulation of Membrane Transport

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