Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

Abstract

Significance: Redox-based signaling governs a number of important pathways in tissue homeostasis. Consequently, deregulation of redox-controlled processes has been linked to a number of human diseases. Among the biological processes regulated by redox signaling, apoptosis or programmed cell death is a highly conserved process important for tissue homeostasis. Apoptosis can be triggered by a wide variety of stimuli, including death receptor ligands, environmental agents, and cytotoxic drugs. Apoptosis has also been implicated in the etiology of many human diseases. Recent Advances: Recent discoveries demonstrate that redox-based changes are required for efficient activation of apoptosis. Among these redox changes, alterations in the abundant thiol, glutathione (GSH), and the oxidative post-translational modification, protein S-glutathionylation (PSSG) have come to the forefront as critical regulators of apoptosis. Critical Issues: Although redox-based changes have been documented in apoptosis and disease pathogenesis, the mechanistic details, whereby redox perturbations intersect with pathogenic processes, remain obscure. Future Directions: Further research will be needed to understand the context in which of the members of the death receptor pathways undergo ligand dependent oxidative modifications. Additional investigation into the interplay between oxidative modifications, redox enzymes, and apoptosis pathway members are also critically needed to improve our understanding how redoxbased control is achieved. Such analyses will be important in understanding the diverse chronic diseases. In this review we will discuss the emerging paradigms in our current understanding of redox-based regulation of apoptosis with an emphasis on S-glutathionylation of proteins and the enzymes involved in this important posttranslational modification. Antioxid. Redox Signal. 16,[496][497][498][499][500][501][502][503][504][505]

GSTO1-1 modulates metabolism in macrophages activated through the LPS and TLR4 pathway

“…Several studies (Anathy et al, 2012;Cooper et al, 2011;Dalle-Donne et al, 2009;Lim et al, 2010) have suggested that protein glutathionylation can provide a reversible switch that can regulate protein function and potentially regulate pathways in a manor analogous to protein phosphorylation. We have previously shown that GSTO1-1 can catalyse glutathionylation cycle reactions (Menon and Board, 2013) and in this study we found that total glutathionylation of proteins was significantly elevated in GSTO1-1-knockdown cells compared with wild-type and non-silencing control cells (Fig.…”

Oxidative Stress Induced S-glutathionylation and Proteolytic Degradation of Mitochondrial Thymidine Kinase 2

“…We do not know which protease is involved in the degradation of TK2 and what implications this may have on mitochondrial function. It is likely that the relevant proteases are either induced or activated in response to oxidative stress and are involved in the redox regulation of mtDNA replication and maintenance (32,33).…”

Glutaredoxin-1 Attenuates S-Glutathionylation of the Death Receptor Fas and Decreases Resolution of Pseudomonas aeruginosa Pneumonia

“…However, a recent body of evidence has emerged in support of a critical regulatory role of oxidants in biologic processes, exerted in part through controlled oxidations of regulatory cysteines within proteins. Protein S-glutathionylation is an example of such cysteine oxidation that under physiologic conditions can be reversed by the protein thiol oxidoreductase, Grx (6). To date, virtually no information exists with regard to the role of Grx1 in the pathogenesis of infectious lung diseases.…”

“…S-glutathionylation is an oxidative modification of protein cysteines that regulates structure and function (6). We have demonstrated that oxidative modification of Fas in the form of S-glutathionylation (Fas-SSG) enhances its ability to form the death-inducing signaling complex and accelerates apoptosis in epithelial cells.…”