Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress

Gallogly, Molly; Mieyal, John J.

doi:10.1016/j.coph.2007.06.003

Cited by 426 publications

(407 citation statements)

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“…113 GRXs are versatile oxidoreductases that use the reducing power of GSH to catalyze reversible protein glutathionylation (reduction of mixed disulfides). Inhibition of GRXs by cadmium induces apoptosis in the absence of any other stimuli, which is associated to increased protein-SSG formation.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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“…The mammalian cytosolic form of Grx (Grx1) is very selective and effective for protein-SSG compared with other forms of disulfides (e.g., S-S disulfide bond, S-nitrosylation, etc. ), and thus is considered as a specific deglutathionylating enzyme (44). Moreover, in Grx1 knockout mice, no deglutathionylating activity is detected (74), further supporting its critical role.…”

Section: Deglutathionylation Enzymesmentioning

confidence: 77%

“…The specificity of protein S-glutathionylation is still under wide debate (31,44,75). In general, it is believed that not all cysteine residues are equally susceptible to S-glutathionylation upon stimuli.…”

Section: Specificity Of Protein S-glutathionylationmentioning

confidence: 99%

“…S-glutathionylation has been found in a large number of proteins, affecting a variety of cellular processes (32,51). Many different thiol modification mechanisms have been associated with oxidative stress but as GSH is naturally abundant within the cells, GSH is likely to serve as a major electron donor, making S-glutathionylation a preferred mechanism for protein modification during oxidative stress (33,44).…”

Section: S-glutathionylation Overviewmentioning

confidence: 99%

“…Oxidative stress, or reactive oxygen species (ROS), facilitates S-glutathionylation. Protein S-glutathionylation has been extensively discussed in many excellent reviews with a variety of different emphases (31,44,45,75,76,88,93,100,107). Over the past few years, S-glutathionylation has been increasingly observed in many ion channels, such as voltage-gated calcium channels, ryanodine receptor (RyR), and ATP-sensitive potassium channels (K ATP channels), all of which contribute to critical cellular functions (4,123,137,138).…”

Section: Introductionmentioning

confidence: 99%

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S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

Yang

Jin²,

Jiang³

2014

Antioxidants & Redox Signaling

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Significance: Ion channels control membrane potential, cellular excitability, and Ca ++ signaling, all of which play essential roles in cellular functions. The regulation of ion channels enables cells to respond to changing environments, and post-translational modification (PTM) is one major regulation mechanism. Recent Advances: Many PTMs (e.g., S-glutathionylation, S-nitrosylation, S-palmitoylation, S-sulfhydration, etc.) targeting the thiol group of cysteine residues have emerged to be essential for ion channels regulation under physiological and pathological conditions. Critical Issues: Under oxidative stress, S-glutathionylation could be a critical PTM that regulates many molecules. In this review, we discuss S-glutathionylation-mediated structural and functional changes of ion channels. Criteria for testing S-glutathionylation, methods and reagents used in ion channel S-glutathionylation studies, and thiol modification crosstalk, are also covered. Mechanotransduction, and S-glutathionylation of the mechanosensitive K ATP channel, are discussed. Future Directions: Further investigation of the ion channel S-glutathionylation, especially the physiological significance of S-glutathionylation and thiol modification crosstalk, could lead to a better understanding of the thiol modifications in general and the ramifications of such modifications on cellular functions and related diseases. Antioxid. Redox Signal. 20, 937-951.

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Mass Spectrometry to Identify Posttranslational Modifications

Eyers¹,

Gaskell²

2008

Wiley Encyclopedia of Chemical Biology

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The analysis of posttranslational modifications using mass spectrometric‐based strategies is a rapidly growing area of postgenome science. This article describes an overview of the techniques currently used in the analysis of some common protein modifications. Strategies are described for the selective enrichment of modified peptides to facilitate mass spectrometric analysis. Techniques are also described for the identification of peptides that carry specific modifications by detection of characteristic fragment ions following collision‐induced dissociation.

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Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress

Cited by 426 publications

References 100 publications

Apoptosis and glutathione: beyond an antioxidant

Apoptosis and glutathione: beyond an antioxidant

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

Mass Spectrometry to Identify Posttranslational Modifications

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