Posttranslational Modification of Cysteine in Redox Signaling and Oxidative Stress: Focus on S-Glutathionylation

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling pathways, and they are known also as deleterious mediators of cellular stress and cell death. ROS and RNS, and their cross products like peroxynitrite, react primarily with cysteine residues whose oxidative modification leads to functional alterations in the proteins. In this Forum, the collection of six review articles presents a perspective on the broad biological impact of cysteine modifications in health and disease from the molecular to the cellular and organismal levels, focusing in particular on reversible protein-S-glutathionylation and its central role in transducing redox signals as well as protecting proteins from irreversible cysteine oxidation. The Forum review articles consider the role of Sglutationylation in regulation of the peroxiredoxin enzymes, the special redox environment of the mitochondria, redox regulation pertinent to the function of the cardiovascular system, mechanisms of redox-activated apoptosis in the pulmonary system, and the role of glutathionylation in the initiation, propagation, and treatment of neurodegenerative diseases. Several common themes emerge from these reviews; notably, the probability of crosstalk between signaling/regulation mechanisms involving protein-S-nitrosylation and protein-S-glutathionylation, and the need for quantitative analysis of the relationship between specific cysteine modifications and corresponding functional changes in various cellular contexts. Antioxid. Redox Signal. 16, 471-475.Historical Perspective S erious consideration of reversible protein glutathionylation as a mechanism of regulation has a relatively brief history, probably less than 30 years. Nevertheless, this focused area of research has captured the imagination of a growing number of biologists, most intensively during the last 10 years. This emergence has been fostered largely by the convergence of understanding about reactive oxygen and reactive nitrogen species as second messengers in signal transduction, the importance of posttranslational modification of cysteine residues, and the special properties of the glutaredoxin (Grx) (thioltransferase) enzyme as a specific catalyst of deglutathionylation of protein-glutathione (GSH) mixed disulfides. An historical perspective on evolution of this focal area of biology can be gleaned from considering a number of key reviews that have appeared over the past 25 years. In reverse chronology, 25 years ago Ziegler presented the point of view that considered protein glutathionylation strictly in the context of thermodynamic redox equilibria coupled to the GSH/glutathione disulfide (GSSG) ratio, and he concluded that reversible glutathionylation as a regulatory phenomenon was highly unlikely (31). According to his premise he was correct, because most cysteine residues have redox potentials that would require the intracellular GSH/GSSG ratio to change from about 100:1 to 1...

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

“…Under these conditions, Prx2 is converted initially to a dimer (Fig. 6, lane 2), and then as the H 2 O 2 is consumed, it is re-reduced by cellular recycling mechanisms (lanes [3][4][5]. When the cells were treated in the presence of dinitrochlorobenzene (DNCB), which inhibits TrxR and reacts with other thiols, recycling was inhibited (lanes 9 -11 and Ref.…”

Glutathionylation State of Uncoupling Protein-2 and the Control of Glucose-stimulated Insulin Secretion

“…Conjugation of GSH to exposed thiol residues, a covalent modification referred to as glutathionylation, also plays a part in redox signaling (28). Indeed, changes in the glutathionylated proteome coincide with alterations in ROS levels that control many mitochondrial and cellular functions, including aerobic metabolism, signaling, and cell division (29,30).…”

Mycothiol protects <i>Corynebacterium glutamicum</i> against acid stress via maintaining intracellular pH homeostasis, scavenging ROS, and <i>S</i>-mycothiolating MetE

“…Protein S-thiolation is a reversible post-translational thiol-modification that protects active site cysteine residues of key enzymes against irreversible overoxidation to sulfonic acids (Dalle-Donne et al, 2009;Shenton and Grant, 2003). S-glutathionylation, a well-documented protein S-thiolation modification formed between cysteine residues and low-molecularweight thiols such as glutathione, is induced in response to oxidative stress in eukaryotic and most GSH containing Gram-negative bacteria cells, and plays important roles in various biological processes, including cell signaling, metabolism and energy, redox homeostasis and protein degradation (Dalle-Donne et al, 2009;Mieyal and Chock, 2012;Shenton and Grant, 2003). Recently, six Sbacillithiolated proteins and 25 S-mycothiolated proteins, formed between cysteine residues and low-molecularweight thiols BSH (S-bacillithiolation) or MSH (Smycothiolation), respectively, were identified upon oxidative stress in B. subtilis and C. glutamicum (Chi et al, 2011(Chi et al, , 2014.…”