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Recruitment of GSH into the nucleus during cell proliferation

ABSTRACT: The essential thiol antioxidant, glutathione (GSH) is recruited into the nucleus of mammalian cells early in cell proliferation, suggesting a key role of the nuclear thiol pool in cell cycle regulation. However, the functions of nuclear GSH (GSHn) and its integration with the cytoplasmic GSH (GSHc) pools in whole cell redox homeostasis and signaling are unknown. Here we show that GSH is recruited into the nucleus early in cell proliferation in Arabidopsis thaliana, confirming the requirement for localization of GSH in the nucleus as a universal feature of cell cycle regulation. GSH accumulation in the nucleus was triggered by treatments that synchronize cells at G1/S as identified by flow cytometry and marker transcripts. Significant decreases in transcripts associated with oxidative signaling and stress tolerance occurred when GSH was localized in the nucleus. Increases in GSH1 and GSH2 transcripts accompanied the large increase in total cellular GSH observed during cell proliferation, but only GSH2 was differentially expressed in cells with high GSHn relative to those with an even intracellular distribution of GSH. Of the 7 Bcl-2 associated (BAG) genes in A. thaliana, only the nuclear-localized BAG 6 was differentially expressed in cells with high GSHn compared to GSHc. We conclude that GSHn is associated with decreased oxidative signaling and stress responses and that whole cell redox homeostasis is restored as the cell cycle progresses by enhanced GSH synthesis and accumulation in the cytoplasm.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE20454 | GEO | 2010/02/22

SECONDARY ACCESSION(S): PRJNA125115

REPOSITORIES: GEO

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Recruitment of GSH into the nucleus during cell proliferation

Project description:The essential thiol antioxidant, glutathione (GSH) is recruited into the nucleus of mammalian cells early in cell proliferation, suggesting a key role of the nuclear thiol pool in cell cycle regulation. However, the functions of nuclear GSH (GSHn) and its integration with the cytoplasmic GSH (GSHc) pools in whole cell redox homeostasis and signaling are unknown. Here we show that GSH is recruited into the nucleus early in cell proliferation in Arabidopsis thaliana, confirming the requirement for localization of GSH in the nucleus as a universal feature of cell cycle regulation. GSH accumulation in the nucleus was triggered by treatments that synchronize cells at G1/S as identified by flow cytometry and marker transcripts. Significant decreases in transcripts associated with oxidative signaling and stress tolerance occurred when GSH was localized in the nucleus. Increases in GSH1 and GSH2 transcripts accompanied the large increase in total cellular GSH observed during cell proliferation, but only GSH2 was differentially expressed in cells with high GSHn relative to those with an even intracellular distribution of GSH. Of the 7 Bcl-2 associated (BAG) genes in A. thaliana, only the nuclear-localized BAG 6 was differentially expressed in cells with high GSHn compared to GSHc. We conclude that GSHn is associated with decreased oxidative signaling and stress responses and that whole cell redox homeostasis is restored as the cell cycle progresses by enhanced GSH synthesis and accumulation in the cytoplasm. Arabidopsis cells were harvested at points during cell proliferation where GSH was localized either in the nucleus (GSHn) or where GSH was distributed throughout the cytoplasm (GSHc) for RNA extraction and hybridization on Affymetrix microarrays. We selected three stages where the GSH was into the nucleus and three stages where the GSH was distributed throughout the cells.

2010-02-27 | E-GEOD-20454 | biostudies-arrayexpress

Degradation of intracellular glutathione in Aspergillus nidulans

Project description:Glutathione (GSH) is an abundant and widely distributed antioxidant in fungi. Hence, understanding cellular GSH metabolism is of vital importance to deciphering redox regulation in these microorganisms. In this study, we generated dugB (AN1879), dugC (AN1092), and dugB dugC double deletion mutants which display disruption of the GSH degradation pathway in Aspergillus nidulans. Deletion of dugB, dugC or both resulted in a moderate increase in GSH content under growing conditions and substantially slowed down the depletion of GSH pools under carbon starvation. Inactivation of dug genes caused reduced accumulation of reactive oxygen species, decreased autolytic cell wall degradation and extracellular enzyme production, increased sterigmatocystin formation but decreased viability in starving cultures. Changes in the transcriptomes suggested that enzyme secretions were controlled at post transcriptional level. In contrast, secondary metabolite production was also regulated at the level of mRNA abundance. Based on these findings, we suggest that GSH connects starvation and redox regulation to each other: A. nidulans cells utilize GSH as stored carbon source during starvation. The reduction of GSH contents of cells alters the redox state activating regulatory pathways responsible for carbon starvation stress responses. Under glucose rich conditions, inactivation of dug genes reduced conidia production of surface cultures, disturbed sexual development and down-regulated the transcription of genes encoding MAP kinase pathway proteins (e.g. steC, sskB, pbsA, hogA, mkkA) or proteins involved in the regulation of conidiogenesis or sexual differentiation (e.g. flbA,C,E, nosA, rosA, nsdC,D). These finding indicates that the authority of redox regulation goes far beyond the protection against redox stress; it affects development, stress responses (other than redox stress) and secondary metabolism as well.

2021-03-02 | GSE151461 | GEO

Nuclear export is a limiting factor in eukaryotic mRNA metabolism

Project description:The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments. We develop a model that reliably quantifies mRNA synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3’UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.

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Click Chemistry-based Thiol Redox Proteomics Reveals Significant Cysteine Reduction Induced by Chronic Ethanol Consumption

Project description:In the U.S., alcohol-associated liver disease (ALD) impacts millions of people and is a major healthcare burden. While the pathology of ALD is unmistakable, the molecular mechanisms underlying ethanol hepatotoxicity are not fully understood. Hepatic ethanol metabolism is intimately linked with alterations in extracellular and intracellular metabolic processes, specifically oxidation/reduction reactions. The xenobiotic detoxification of ethanol leads to significant disruptions in glycolysis, β-oxidation, and the TCA cycle, as well as oxidative stress. Perturbation of these regulatory networks impacts the redox status of critical regulatory protein thiols throughout the cell. Integrating these key concepts, our goal was to apply a cutting-edge approach toward understanding mechanisms of ethanol metabolism in disrupting hepatic thiol redox signaling. Utilizing a chronic murine model of ALD, we applied a cysteine targeted click chemistry enrichment coupled with quantitative nHPLC-MS/MS to assess the thiol redox proteome. Our strategy reveals that ethanol metabolism largely reduces the cysteine proteome, with 593 cysteine residues significantly reduced and 8 significantly oxidized cysteines. Ingenuity Pathway Analysis demonstrates that ethanol metabolism reduces specific cysteines throughout ethanol metabolism (Adh1, Cat, Aldh2), antioxidant pathways (Prx1, Mgst1, Gsr), as well as many other biochemical pathways. Further research is needed to determine how a reduced cysteine proteome impacts individual protein activity across these protein targets and pathways. Additionally, understanding how a complex array of cysteine-targeted post-translational modifications (e.g., S-NO, S-GSH, S-OH) are integrated to regulate redox signaling and control throughout the cell is key to the development of redox-centric therapeutic agents targeted to ameliorate the progression of ALD.

2024-09-19 | PXD042070 | Pride

Global and mitochondrial proteomics under GSH depletion

Project description:Glutathione (GSH) is a tripeptide thiol abundantly present in all eukaryotes1. As the major site of oxidative metabolism, mitochondria must maintain sufficient levels of GSH in order to perform key protective and biosynthetic functions. GSH is exclusively synthesized in the cytosol, yet how it enters mitochondria and the molecular machinery involved in mitochondrial GSH import remain elusive. Here, using mass-spectrometry approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, to mediate GSH transport into mitochondria. SLC25A39 loss reduces mitochondrial GSH import and abundance, without impacting whole cell GSH levels.

2021-11-15 | PXD027673 | Pride

Transcription profiling of Arabidopsis leaves reponse to DTT to examine the effect of redox on gene expression

Project description:In this study, we used GC-MS analysis in combination with flux analysis and the Affymetrix ATH1 GeneChip to survey the metabolome and transcriptome of Arabidopsis leaves in response to manipulation of the thiol-disulfide status. Feeding low concentrations of the sulfhydryl reagent dithiothreitol (DTT) for one hour at the end of the dark period led to post-translational redox-activation of ADP-glucose pyrophosphorylase and major alterations in leaf carbon partitioning, including an increased flux into major respiratory pathways, starch- cell-wall-, and amino-acid synthesis and a reduced flux to sucrose. This was accompanied by a decrease in the levels of hexose-phosphates, while metabolites in the second half of the TCA cycle and various amino acids increased, indicating a stimulation of anaplerotic fluxes reliant on Î±-ketoglutarate. There was also an increase in shikimate as a precursor of secondary plant products and marked changes in the levels of the minor sugars involved in ascorbate synthesis and cell wall metabolism. Transcript profiling revealed a relatively small number of changes in the levels of transcripts coding for components of redox-regulation, transport processes and cell wall, protein and amino acid metabolism, while there were no major alterations in transcript levels coding for enzymes involved in central metabolic pathways. These results provide a global picture of the effect of redox and reveal the utility of transcript and metabolite profiling as systemic strategies to uncover the occurrence of redox-modulation in vivo. Experiment Overall Design: Leaf discs were incubated with or without 5mM DTT for one hour to affect the redox status of the cells. The effect of this treatment on global gene expression was analysed using affymetrix ATH1 microarrays. The experiments contains one control (-DTT) and one treatment (+DTT) and is performed with 2 biological replicas.

2008-06-12 | E-GEOD-4021 | biostudies-arrayexpress

Expression of Heterologous OsDHAR Gene Improves Glutathione (GSH)-Dependent Antioxidant System and Maintenance of Cellular Redox Status in Synechococcus elongatus PCC 7942

Project description:An excess of reactive oxygen species (ROS) can cause severe oxidative damage to cellular components in photosynthetic cells. Antioxidant systems, such as the ascorbate-glutathione cycle, regulate redox status in cells to guard against such damage. Dehydroascorbate reductase (DHAR, EC 1.8.5.1) catalyzes the glutathione-dependent reduction of oxidized ascorbate (dehydroascorbate) and contains a redox active site and glutathione binding-site. The DHAR gene is important in biological and abiotic stress responses involving reduction of the oxidative damage caused by ROS. In this study, a transgenic microalgae (TA) strain was constructed by cloning the Oryza sativa L. japonica DHAR (OsDHAR) gene controlled by an isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible promoter (Ptrc) into the Synechococcus elongatus PCC 7942 strain of cyanobacteria to study the functional activities of OsDHAR under oxidative stress caused by hydrogen peroxide exposure. OsDHAR expression increased the growth of S. elongatus PCC 7942 under oxidative stress by reducing the levels of hydroperoxides and malondialdehyde (MDA) and mitigating the loss of chlorophyll. DHAR and glutathione S-transferase activity were higher than in the wild-type (WT) strain. Additionally, overexpression of OsDHAR in S. elongatus PCC 7942 greatly increased the glutathione (GSH)/glutathione disulfide (GSSG) ratio compared to ascorbic acid (AsA)/dehydroascorbate (DHA) ratio in the presence or absence of hydrogen peroxide. These results strongly suggest that DHAR attenuates deleterious oxidative effects via the glutathione (GSH)-dependent antioxidant system in cyanobacterial cells. The expression of heterologous OsDHAR in S. elongatus PCC 7942 protected cells from oxidative damage through a GSH-dependent antioxidant system via GSH-dependent reactions at the redox active site and GSH binding site residues during oxidative stress.

2019-11-25 | GSE140121 | GEO

Arabidopsis thaliana

Project description:Recruitment of GSH into the nucleus during cell proliferation

| PRJNA125115 | ENA

effect of redox on gene expression

Project description:In this study, we used GC-MS analysis in combination with flux analysis and the Affymetrix ATH1 GeneChip to survey the metabolome and transcriptome of Arabidopsis leaves in response to manipulation of the thiol-disulfide status. Feeding low concentrations of the sulfhydryl reagent dithiothreitol (DTT) for one hour at the end of the dark period led to post-translational redox-activation of ADP-glucose pyrophosphorylase and major alterations in leaf carbon partitioning, including an increased flux into major respiratory pathways, starch- cell-wall-, and amino-acid synthesis and a reduced flux to sucrose. This was accompanied by a decrease in the levels of hexose-phosphates, while metabolites in the second half of the TCA cycle and various amino acids increased, indicating a stimulation of anaplerotic fluxes reliant on α-ketoglutarate. There was also an increase in shikimate as a precursor of secondary plant products and marked changes in the levels of the minor sugars involved in ascorbate synthesis and cell wall metabolism. Transcript profiling revealed a relatively small number of changes in the levels of transcripts coding for components of redox-regulation, transport processes and cell wall, protein and amino acid metabolism, while there were no major alterations in transcript levels coding for enzymes involved in central metabolic pathways. These results provide a global picture of the effect of redox and reveal the utility of transcript and metabolite profiling as systemic strategies to uncover the occurrence of redox-modulation in vivo. Keywords: redox regulation

2006-04-10 | GSE4021 | GEO

Redox regulation of auxin and strigolactone signaling in the control of Arabidopsis thaliana root growth

Project description:Reduced glutathione (GSH) is required for cell cycle initiation and auxin-regulated root meristem development. Transcriptome profiling of the roots and shoots of the root meristemless 1 (rml1) mutant, which has about 3% of the wild type GSH, revealed a divergent auxin and strigolactone response linked to the arrest of the cell cycle.

2013-01-10 | GSE36893 | GEO

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