Molecular Mechanisms and Clinical Implications of Reversible ProteinS-Glutathionylation

Abstract

Sulfhydryl chemistry plays a vital role in normal biology and in defense of cells against oxidants, free radicals, and electrophiles. Modification of critical cysteine residues is an important mechanism of signal transduction, and perturbation of thiol-disulfide homeostasis is an important consequence of many diseases. A prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein-SSG) with glutathione (GSH). The abundance of GSH in cells and the ready conversion of sulfenic acids and S-nitroso derivatives to S-glutathione mixed disulfides suggests that reversible S-glutathionylation may be a common feature of redox signal transduction and regulation of the activities of redox sensitive thiol-proteins. The glutaredoxin enzyme has served as a focal point and important tool for evolution of this regulatory mechanism, because it is a specific and efficient catalyst of protein-SSG de-glutathionylation. However, mechanisms of control of intracellular GRx activity in response to various stimuli are not well understood, and delineation of specific mechanisms and enzyme(s) involved in formation of protein-SSG intermediates requires further attention. A large number of proteins have been identified as potentially regulated by reversible S-glutathionylation, but only a few studies have documented glutathionylation-dependent changes in activity of specific proteins in a physiological context. Oxidative stress is a hallmark of many diseases which may interrupt or divert normal redox signaling and perturb protein-thiol homeostasis. Examples involving changes in S-glutathionylation of specific proteins are discussed in the context of diabetes, cardiovascular and lung diseases, cancer, and neurodegenerative diseases.

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

“…Glutathione (GSH) is the most abundant non-protein cellular antioxidant, which together with its corresponding disulfide, GSH disulfide (GSSG), modulates intracellular redox status (Mieyal et al, 2008;Townsend, 2007). Both oxidative and nitrosative stresses lead to changes in the ratio of GSH-GSSG and thereby cause posttranslational modifications on redox-sensitive cysteine residues that include S-glutathionylation, S-nitrosylation, or S-oxidation of cellular proteins.…”

Upregulation of NF-E2-related factor-2-dependent glutathione by carnosol provokes a cytoprotective response and enhances cell survival

“…Previous studies have demonstrated that changes in the thiol redox state of the cell might affect the posttranslational modification of p65, including the phosphorylation of critical residues shown to contribute to the nuclear import of this molecule [33,34] . Moreover, a recent study has revealed that a number of redox-sensitive transcription factors are modified by GSH and thereby inhibit their function [35] . The p65 modification by GSH is thus implicated as an inhibitory mechanism by which carnosol regulates NF-κB activation through the increase in GSH levels.…”

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

“…Glutaredoxin (Grx) is suggested to be a major deglutathionylation enzyme in mammalian cells (74,76). 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.…”

“…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).…”