Molecular Mechanisms and Potential Clinical Significance ofS-Glutathionylation

Abstract

Protein S-glutathionylation, the reversible binding of glutathione to protein thiols (PSH), is involved in protein redox regulation, storage of glutathione, and protection of PSH from irreversible oxidation. S-Glutathionylated protein (PSSG) can result from thiol/disulfide exchange between PSH and GSSG or PSSG; direct interaction between partially oxidized PSH and GSH; reactions between PSH and S-nitrosothiols, oxidized forms of GSH, or glutathione thiyl radical. Indeed, thiol/disulfide exchange is an unlikely intracellular mechanism for S-glutathionylation, because of the redox potential of most Cys residues and the GSSG export by most cells as a protective mechanism against oxidative stress. S-Glutathionylation can be reversed, following restoration of a reducing GSH/GSSG ratio, in an enzyme-dependent or -independent manner. Currently, definite evidence of protein S-glutathionylation has been clearly demonstrated in few human diseases. In aging human lenses, protein S-glutathionylation increases; during cataractogenesis, some of lens proteins, including alpha- and beta-crystallins, form both mixed disulfides and disulfide-cross-linked aggregates, which increase with cataract severity. The correlation of lens nuclear color and opalescence intensity with protein S-glutathionylation indicates that protein-thiol mixed disulfides may play an important role in cataractogenesis and development of brunescence in human lenses. Recently, specific PSSG have been identified in the inferior parietal lobule in Alzheimer's disease. However, much investigation is needed to clarify the actual involvement of protein S-glutathionylation in many human diseases.

Apoptosis and glutathione: beyond an antioxidant

“…Hence, GRXs are capable of catalyzing both glutathionylation and deglutathionylation of proteins through distinct mechanisms. 120 Thus, the role of both GRXs and protein-SSG formation needs to be simultaneously assessed to understand their specific involvement during apoptosis. Although GRXs have been shown to have a protective effect against apoptosis by decreasing protein-SSG formation, knockdown of GRX1 was recently reported to significantly inhibited TNF-a-induced cell death because of attenuated caspase 3 cleavage and increased glutathionylation.…”

Serum S-glutathionylated proteins as a potential biomarker of carotid artery stenosis

“…Protein S-glutathionylation levels increase under conditions of oxidative stress and are controlled by glutaredoxins (GRX) that, under physiological conditions, preferentially deglutathionylate cysteines and restore sulfhydryls [27]. An impairment of redox regulation implies an increase in the susceptibility of compromised individuals to oxidative stress [28].…”

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

“…S-glutathionylation is a PTM of proteins at the cysteine residues by adding a GSH moiety (31). Protein S-glutathionylation may occur in physiological conditions but is generally facilitated by oxidative stress when excessive ROS are present and GSH is locally available to the target protein (33).…”

“…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).…”