Glutathione S-Transferases Interact with AMP-Activated Protein Kinase: Evidence for S-Glutathionylation and Activation In Vitro

Klaus, Anna; Zorman, Sarah; Berthier, Alexandre; Polge, Cécile; Ramirez, Sacnicte; Michelland, Sylvie; Sève, Michel; Vertommen, Didier; Rider, Mark H.; Lentze, Nicolas; Auerbach, Daniel; Schlattner, Uwe

doi:10.1371/journal.pone.0062497

Cited by 59 publications

(42 citation statements)

References 64 publications

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“…Although there is a degree of redundancy within the GST family, GSTP is the most highly expressed isozyme in MEF cells and BMDDC and influences the doubling time of these cells (39,61) and remains the only isoform to exhibit thiolase activity (28,51,52). Our present results show a significant difference in levels of innate resistance of the Gstp1/p2 +/+ and Gstp1/p2…”

Section: Discussionmentioning

confidence: 99%

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Zhang

Ancrum

et al. 2017

Antioxidants & Redox Signaling

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Aims: S-glutathionylation of cysteine residues, catalyzed by glutathione S-transferase Pi (GSTP), alters structure/function characteristics of certain targeted proteins. Our goal is to characterize how S-glutathionylation of proteins within the endoplasmic reticulum (ER) impact cell sensitivity to ER-stress inducing drugs. Results: We identify GSTP to be an ER-resident protein where it demonstrates both chaperone and catalytic functions. Redox based proteomic analyses identified a cluster of proteins cooperatively involved in the regulation of ER stress (immunoglobulin heavy chain-binding protein [BiP], protein disulfide isomerase [PDI], calnexin, calreticulin, endoplasmin, sarco/endoplasmic reticulum Ca 2+ -ATPase [SERCA]) that individually coimmunoprecipitated with GSTP (implying protein complex formation) and were subject to reactive oxygen species (ROS) induced S-glutathionylation. S-glutathionylation of each of these six proteins was attenuated in cells (liver, embryo fibroblasts or bone marrow dendritic) from mice lacking GSTP (Gstp1/p2 -/-) compared to wild type (Gstp1/p2 +/+ ). Moreover, Gstp1/p2 -/-cells were significantly more sensitive to the cytotoxic effects of the ER-stress inducing drugs, thapsigargin (7-fold) and tunicamycin (2-fold). Innovation: Within the family of GST isozymes, GSTP has been ascribed the broadest range of catalytic and chaperone functions. Now, for the first time, we identify it as an ER resident protein that catalyzes S-glutathionylation of critical ER proteins within this organelle. Of note, this can provide a nexus for linkage of redox based signaling and pathways that regulate the unfolded protein response (UPR). This has novel importance in determining how some drugs kill cancer cells. Conclusions: Contextually, these results provide mechanistic evidence that GSTP can exert redox regulation in the oxidative ER environment and indicate that, within the ER, GSTP influences the cellular consequences of the UPR through S-glutathionylation of a series of key interrelated proteins. Antioxid. Redox Signal. 26, 247-261.

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Section: Discussionmentioning

confidence: 99%

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Zhang

Ancrum

et al. 2017

Antioxidants & Redox Signaling

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“…Briefly, loss of GRX2 can compromise mitochondrial respiration and ATP production and alter O 2˙− /H 2 O 2 production, which is associated with the development of heart disease, hypertension, cataracts, and perturbations in embryonic development. In addition to the glutaredoxin enzymes, it has also been found that glutathione S-transferase can catalyze the reversible S-glutathionylation of cellular proteins (Klaus et al, 2013). Pi and Mu-members of the GST family have been found to catalyze the S-glutathionylation of AMP kinase, the master energy gauge for the cell (Klaus et al, 2013).…”

Section: Controlling Mitochondrial Ros Production By Redox Signalsmentioning

confidence: 99%

“…In addition to the glutaredoxin enzymes, it has also been found that glutathione S-transferase can catalyze the reversible S-glutathionylation of cellular proteins (Klaus et al, 2013). Pi and Mu-members of the GST family have been found to catalyze the S-glutathionylation of AMP kinase, the master energy gauge for the cell (Klaus et al, 2013). It remains to be determined if GST isoforms are also required to catalyze these reactions in mitochondria.…”

Section: Controlling Mitochondrial Ros Production By Redox Signalsmentioning

confidence: 99%

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Kuksal

Chalker

Mailloux

2017

Biological Chemistry

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Abstract:The molecular oxygen (O 2 ) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O 2 is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H 2 O 2 , are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H 2 O 2 elimination pathways are well characterized in mitochondria. However, less is known about how H 2 O 2 production is controlled. The present review examines the importance of mitochondrial H 2 O 2 in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H 2 O 2 can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H 2 O 2 production.

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“…However, the role of this GSTp S-glutathionylation or the interaction of GSTp with Prx proteins in facilitating Sglutathionylation of target proteins remains unknown. Nonetheless, mouse embryonic fibroblasts (MEFs) from GSTp Using a yeast two-hybrid assay, GSTp was reported to interact with AMP-activated protein kinase (AMPK), an interaction that occurs in vitro and in liver tissue lysates (108). In vitro, GSTp facilitates the S-glutathionylation of AMPK in the presence of low concentrations of GSH, and this Sglutathionylation enhances AMPK kinase activity independent of AMPK phosphorylation (108).…”

mentioning

confidence: 99%

“…Nonetheless, mouse embryonic fibroblasts (MEFs) from GSTp Using a yeast two-hybrid assay, GSTp was reported to interact with AMP-activated protein kinase (AMPK), an interaction that occurs in vitro and in liver tissue lysates (108). In vitro, GSTp facilitates the S-glutathionylation of AMPK in the presence of low concentrations of GSH, and this Sglutathionylation enhances AMPK kinase activity independent of AMPK phosphorylation (108). In addition, inhibition of GSTp in C10 murine alveolar epithelial cells with TLK-199 or siRNA blocks S-glutathionylation of the Fas ligand (FasL) in response to FasL stimulation (10), suggesting that GSTp plays a role in the FasL autoregulatory loop involving protein-S-glutathionylation.…”

mentioning

confidence: 99%

Protein Thiol Redox Signaling in Monocytes and Macrophages

Short

Downs

Tavakoli

et al. 2016

Antioxidants & Redox Signaling

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Significance: Monocyte and macrophage dysfunction plays a critical role in a wide range of inflammatory disease processes, including obesity, impaired wound healing diabetic complications, and atherosclerosis. Emerging evidence suggests that the earliest events in monocyte or macrophage dysregulation include elevated reactive oxygen species production, thiol modifications, and disruption of redox-sensitive signaling pathways. This review focuses on the current state of research in thiol redox signaling in monocytes and macrophages, including (i) the molecular mechanisms by which reversible protein-S-glutathionylation occurs, (ii) the identification of bona fide S-glutathionylated proteins that occur under physiological conditions, and (iii) how disruptions of thiol redox signaling affect monocyte and macrophage functions and contribute to atherosclerosis. Recent Advances: Recent advances in redox biochemistry and biology as well as redox proteomic techniques have led to the identification of many new thiol redox-regulated proteins and pathways. In addition, major advances have been made in expanding the list of S-glutathionylated proteins and assessing the role that protein-S-glutathionylation and S-glutathionylation-regulating enzymes play in monocyte and macrophage functions, including monocyte transmigration, macrophage polarization, foam cell formation, and macrophage cell death. Critical Issues: Protein-S-glutathionylation/deglutathionylation in monocytes and macrophages has emerged as a new and important signaling paradigm, which provides a molecular basis for the well-established relationship between metabolic disorders, oxidative stress, and cardiovascular diseases. Future Directions: The identification of specific S-glutathionylated proteins as well as the mechanisms that control this post-translational protein modification in monocytes and macrophages will facilitate the development of new preventive and therapeutic strategies to combat atherosclerosis and other metabolic diseases. Antioxid. Redox Signal. 25,[816][817][818][819][820][821][822][823][824][825][826][827][828][829][830][831][832][833][834][835]

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Glutathione S-Transferases Interact with AMP-Activated Protein Kinase: Evidence for S-Glutathionylation and Activation In Vitro

Cited by 59 publications

References 64 publications

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Protein Thiol Redox Signaling in Monocytes and Macrophages

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