Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

Hildebrandt, Thomas B.; Knuesting, Johannes; Berndt, Carsten; Morgan, Bruce; Scheibe, Renate

doi:10.1515/hsz-2014-0295

Cited by 151 publications

(136 citation statements)

References 102 publications

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…Precedents exist for distinct biochemical activities (for a given protein) that are dependent on specific redox modifications. The catalytic cysteine of cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is susceptible to a variety of reversible thiol modifications, including sulfenylation, glutathionylation, nitrosylation, and sulfhydration (37)(38)(39)(40)(41); as a consequence of distinct modification inputs, GAPDH transduces alternative signals for adaptive adjustment of metabolism or cell death (42). Yet, for BiP, we observe similar activity changes for glutathionylated and sulfenylated BiP.…”

Section: Discussionmentioning

confidence: 80%

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Wang

Sevier

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Redox fluctuations within cells can be detrimental to cell function. To gain insight into how cells normally buffer against redox changes to maintain cell function, we have focused on elucidating the signaling pathways that serve to sense and respond to oxidative redox stress within the endoplasmic reticulum (ER) using yeast as a model system. Previously, we have shown that a cysteine in the molecular chaperone BiP, a Hsp70 molecular chaperone within the ER, is susceptible to oxidation by peroxide during ER-derived oxidative stress, forming a sulfenic acid (؊SOH) moiety. Here, we demonstrate that this same conserved BiP cysteine is susceptible also to glutathione modification (؊SSG). Glutathionylated BiP is detected both as a consequence of enhanced levels of cellular peroxide and also as a by-product of increased levels of oxidized glutathione (GSSG). Similar to sulfenylation, we observe glutathionylation decouples BiP ATPase and peptide binding activities, turning BiP from an ATP-dependent foldase into an ATP-independent holdase. We show glutathionylation enhances cell proliferation during oxidative stress, which we suggest relates to modified BiP's increased ability to limit polypeptide aggregation. We propose the susceptibility of BiP to modification with glutathione may serve also to prevent irreversible oxidation of BiP by peroxide.Cell homeostasis and numerous vital cell functions rely on the maintenance of a proper intracellular redox balance. Oxidative folding in the endoplasmic reticulum (ER) 2 is one intracellular system that is prone to disruption upon alterations in the redox poise. Insufficient oxidizing capacity in the ER leads to the accumulation of proteins in reduced non-native states (1, 2). Alternatively, an overly oxidizing ER results in cellular toxicity, likely caused in part by the mis-pairing of protein cysteine residues resulting from a decreased capacity to reduce nonnative disulfides (3, 4). Crucial for maintaining a continual flux of folding polypeptides through the ER are the systems that buffer against fluctuations in the ER redox environment.Recently, several proteins have been demonstrated to act as sensors of redox fluctuations in the ER. In a common theme, these proteins sense changes in the ER redox environment and respond with beneficial alterations in their enzymatic activities. The enzyme Ero1 is a major source of oxidizing equivalents in the ER, and Ero1 activity is coupled to the ER redox environment. When the ER balance shifts to overly oxidizing conditions, regulatory cysteine residues in Ero1 become oxidized to disulfides, which decreases Ero1 oxidase activity to help restore redox balance (5-7). In addition, sensors that cope with the potential for protein folding defects have emerged. These redox-dependent chaperones do not directly impact the flux of oxidizing equivalents, like Ero1, but rather are activated to help limit polypeptide aggregation during unfavorable redox conditions. Oxidation of active site cysteines in the oxidoreductase PDI has been demonstrated to...

show abstract

Section: Discussionmentioning

confidence: 80%

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Wang

Sevier

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…While our isotopic tracing data clearly indicate that GSTP1 inhibition leads to an impairment in the ATP-generating steps of glycolysis downstream of GAPDH, we do not yet understand the mechanism through which this occurs. GAPDH activity is dependent on a highly reactive catalytic cysteine that coordinates the interconversion between 1,3-bisphosphoglycerate into glyceraldehyde-3-phosphate and is particularly sensitive to oxidation by agents such as hydrogen peroxide or other oxidants which can inhibit GAPDH activity (Hildebrandt et al, 2015). Reports have also shown that GAPDH can even be inhibited by its reactive 1,3-bisphosphoglycerate product on a hyper-reactive and functional lysine to inhibit its activity (Moellering and Cravatt, 2013).…”

Section: Discussionmentioning

confidence: 99%

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

Louie

Grossman

Crawford

et al. 2016

Cell Chemical Biology

127

142

View full text Add to dashboard Cite

Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell-types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione-S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.

show abstract

“…The nuclear function of GAPDH in plant systems is not clear, but it probably acts as a coactivator of NADP-MDH expression by binding to the NADP-malate dehydrogenase (NADP-MDH) gene and, consequently, increases the capacity of the malate valve to balance the cellular energy supply (Scheibe 2004, Becker et al 2006, Hildebrandt et al 2015.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Regulates the Cytosolic/Nuclear Partitioning of Glyceraldehyde-3-Phosphate Dehydrogenase by Enhancing its Nuclear Localization

Aroca

Schneider

Scheibe

et al. 2017

Plant and Cell Physiology

Self Cite

View full text Add to dashboard Cite

Hydrogen sulfide is an important signaling molecule comparable with nitric oxide and hydrogen peroxide in plants. The underlying mechanism of its action is unknown, although it has been proposed to be S-sulfhydration. This post-translational modification converts the thiol groups of cysteines within proteins to persulfides, resulting in functional changes of the proteins. In Arabidopsis thaliana, Ssulfhydrated proteins have been identified, including the cytosolic isoforms of glyceraldehyde-3-phosphate dehydrogenase GapC1 and GapC2. In this work, we studied the regulation of sulfide on the subcellular localization of these proteins using two different approaches. We generated GapC1-green fluorescent protein (GFP) and GapC2-GFP transgenic plants in both the wild type and the des1 mutant defective in the L-cysteine desulfhydrase DES1, responsible for the generation of sulfide in the cytosol. The GFP signal was detected in the cytoplasm and the nucleus of epidermal cells, although with reduced nuclear localization in des1 compared with the wild type, and exogenous sulfide treatment resulted in similar signals in nuclei in both backgrounds. The second approach consisted of the immunoblot analysis of the GapC endogenous proteins in enriched nuclear and cytosolic protein extracts, and similar results were obtained. A significant reduction in the total amount of GapC in des1 in comparison with the wild type was determined and exogenous sulfide significantly increased the protein levels in the nuclei in both plants, with a stronger response in the wild type. Moreover, the presence of an Ssulfhydrated cysteine residue on GapC1 was demonstrated by mass spectrometry. We conclude that sulfide enhances the nuclear localization of glyceraldehyde-3-phosphate dehydrogenase.

show abstract

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

Cited by 151 publications

References 102 publications

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

Hydrogen Sulfide Regulates the Cytosolic/Nuclear Partitioning of Glyceraldehyde-3-Phosphate Dehydrogenase by Enhancing its Nuclear Localization

Contact Info

Product

Resources

About