Review
Protein S-glutathionylation: a regulatory device from bacteria to humans

https://doi.org/10.1016/j.tibs.2008.11.002Get rights and content

S-Glutathionylation is the specific post-translational modification of protein cysteine residues by the addition of the tripeptide glutathione, the most abundant and important low-molecular-mass thiol within most cell types. Protein S-glutathionylation is promoted by oxidative or nitrosative stress but also occurs in unstressed cells. It can serve to regulate a variety of cellular processes by modulating protein function and to prevent irreversible oxidation of protein thiols. Recent findings support an essential role for S-glutathionylation in the control of cell-signalling pathways associated with viral infections and with tumour necrosis factor-(-induced apoptosis. Glyceraldehyde-3-phosphate dehydrogenase has recently been implicated in the regulation of endothelin-1 synthesis by a novel, S-glutathionylation-based mechanism involving messenger RNA stability. Moreover, recent studies have identified S-glutathionylation as a redox signalling mechanism in plants.

Section snippets

Cellular thiols

Thiols are a class of organic sulphur derivatives (mercaptans) characterized by the presence of sulphydryl groups (-SH) at their reactive centre. In biological systems, thiols have numerous functions including a central role in coordinating the antioxidant defence network. Biological thiols can be classified as large-molecular-mass protein thiols and low-molecular-mass free (non-protein) thiols (such as glutathione, cysteine and dihydrolipoic acid) [1]. Overall, the thiol redox state reflects

Post-translational modifications of protein thiols: a footprint of oxidative damage or a redox-regulation mechanism?

PSHs are particularly susceptible to oxidative modifications and can undergo a diverse array of redox reactions (Figure 1), which are largely dependent on the species and concentration of the oxidants they contact. In the presence of increasing ROS concentrations and an oxidative cellular environment, PSH can be oxidised into sulphenic (PSOH), sulphinic (PSO2H) or sulphonic (PSO3H) acids. Whereas the formation of PSOH can be reversed, for example by GSH, the two latter species are usually

Role for protein S-glutathionylation in energy metabolism

Various studies enabled the identification of different metabolic enzymes susceptible to redox regulation by S-glutathionylation. The glycolytic enzyme, GAPDH, which has a primary role in energy production and in a variety of crucial nuclear pathways including regulation of apoptosis, DNA repair or nuclear RNA export, was shown to be inactivated by S-glutathionylation (the extent of which was enhanced by GAPDH pre-treatment with H2O2) in an in vitro system using the purified human enzyme and

Role for protein S-glutathionylation in signalling

Many signalling molecules and transcription factors fundamental for cell growth, differentiation and apoptosis are regulated by S-glutathionylation. S-Glutathionylation plays a key part in the regulation of the kinase activity of PTP1B [24] and MEKK1 in response to oxidative stresses [20]. In the rat alveolar macrophage NR8383 cell line, ROS produced through the ADP-stimulated respiratory burst induce the formation of a disulphide bond between PTP1B and GSH [24]. Although previous studies

Role for protein S-glutathionylation in regulating redox homeostasis

In contrast to several other enzymes inhibited by S-glutathionylation of a cysteine in their active site, the temporary inhibition of Trx in human peripheral blood mononuclear cells exposed to diamide was found to occur owing to S-glutathionylation on a cysteine distinct from those of the active site [63].

The study of S-glutathionylation of chloroplastic Trxs from A. thaliana and the green alga Chlamydomonas reinhardtii after treatment with GSSG revealed that f-type Trxs (Trxfs) are the only

Role for protein S-glutathionylation in regulating calcium homeostasis and ion channel activity

S100A1, preferentially expressed in myocardial tissue, is a typical representative of a group of EF-hand calcium-binding proteins known as the S100 family. The protein is composed of two ( subunits, each containing two calcium-binding loops (C and N). The affinity of S100A1 protein for calcium is drastically enhanced when the Cys85 thiol of its ( subunits forms mixed disulphide upon exposure to excess GSSG in vitro; Cys85 S-glutathionylation leads to a tenfold increase in the affinity of the

Role for protein S-glutathionylation in regulating cytoskeletal assembly

Cytoskeletal arrangements and intracellular trafficking can also be regulated by S-glutathionylation. Indeed, growth-factor-mediated actin polymerisation into filaments, translocation to the cell periphery and membrane ruffling are physiologically regulated by S-glutathionylation and deglutathionylation, the effect of which on actin assembly has been demonstrated in vitro 15, 70, 71, 72. Moreover, actin S-glutathionylation induced by ROS generated by integrin receptors during integrin-mediated

Role for protein S-glutathionylation in regulating protein folding and stability

Thimet oligopeptidase is a ubiquitously distributed thiol-rich mammalian metallopeptidase involved in oligopeptide metabolism both outside and within cells, where it was shown to have an important intracellular role in the degradation of peptides released by the 26S proteasome. Mammalian thimet oligopeptidase is constitutively S-glutathionylated inside cells. As demonstrated by experiments performed in vitro, S-glutathionylation is needed for full peptidase activity and controls thimet

Future perspectives and open questions

GSH plays a central part in the cellular defence against oxidative damage in mammalian and plant cells, yeast and some bacteria (Box 2). In living organisms, the initial cellular response to oxidative stress is often a reduction in the level of GSH and a corresponding increase in the level of GSSG. Thus, the oxidation of a limited amount of GSH to GSSG has the potential to drastically change the GSH:GSSG ratio and affect the cellular redox status, although the impact of the export of GSSG or

Acknowledgements

Owing to space limitations, it was not possible to cite all research papers relevant to the presented subject. We sincerely apologize to those authors whose work we could not include. Our research was supported by FIRST 2007 (Fondo Interno Ricerca Scientifica e Tecnologica, University of Milan; www.unimi.it/ENG) and by Fondazione Ariel (Centro per le Disabilità Neuromotorie Infantili, Milan, Italy; www.fondazioneariel.it). Figures included in this review article were prepared using and

References (90)

  • M.D. Shelton et al.

    Regulation by reversible S-glutathionylation: molecular targets implicated in inflammatory diseases

    Mol. Cells

    (2008)
  • A. Rinna

    Stimulation of the alveolar macrophage respiratory burst by ADP causes selective glutathionylation of protein tyrosine phosphatase 1B

    Free Radic. Biol. Med.

    (2006)
  • H.A. Woo

    Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins

    J. Biol. Chem.

    (2005)
  • Z. Huang

    Inhibition of caspase-3 activity and activation by protein glutathionylation

    Biochem. Pharmacol.

    (2008)
  • Y.M. Janssen-Heininger

    Redox-based regulation of signal transduction: principles, pitfalls, and promises

    Free Radic. Biol. Med.

    (2008)
  • M.M. Gallogly et al.

    Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress

    Curr. Opin. Pharmacol.

    (2007)
  • M.J. Peltoniemi

    Insights into deglutathionylation reactions. Different intermediates in the glutaredoxin and protein disulfide isomerase catalyzed reactions are defined by the γ-linkage present in glutathione

    J. Biol. Chem.

    (2006)
  • D.W. Starke

    Glutathione-thiyl radical scavenging and transferase properties of human glutaredoxin (thioltransferase). Potential role in redox signal transduction

    J. Biol. Chem.

    (2003)
  • I.A. Cotgreave

    S-glutathionylation of glyceraldehyde-3-phosphate dehydrogenase: role of thiol oxidation and catalysis by glutaredoxin

    Methods Enzymol.

    (2002)
  • I.S. Kil et al.

    Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation

    J. Biol. Chem.

    (2005)
  • T.R. Hurd

    Complex I within oxidatively stressed bovine heart mitochondria is glutathionylated on Cys-531 and Cys-704 of the 75-kDa subunit: potential role of Cys residues in decreasing oxidative damage

    J. Biol. Chem.

    (2008)
  • M.D. Shelton

    Glutaredoxin regulates nuclear factor (B and intercellular adhesion molecole in Muller cells: model of diabetic retinopathy

    J. Biol. Chem.

    (2007)
  • X. Cao

    Glutathionylation of two cysteine residues in paired domain regulates DNA binding activity of Pax-8

    J. Biol. Chem.

    (2005)
  • L. Codutti

    The solution structure of DNA-free Pax-8 Paired Box domain accounts for redox regulation of transcriptional activity in Pax protein family

    J. Biol. Chem.

    (2008)
  • D.R. Pimentel

    Strain-stimulated hypertrophy in cardiac myocytes is mediated by reactive oxygen species-dependent Ras S-glutathiolation

    J. Mol. Cell. Cardiol.

    (2006)
  • A.P. Fernandes

    A novel monothiol glutaredoxin (Grx4) from Escherichia coli can serve as a substrate for thioredoxin reductase

    J. Biol. Chem.

    (2005)
  • G. Sanchez

    Tachycardia increases NADPH oxidase activity and RyR2 S-glutathionylation in ventricular muscle

    J. Mol. Cell. Cardiol.

    (2005)
  • C. Hidalgo

    A transverse tubule NADPH oxidase activity stimulates calcium release from isolated triads via ryanodine receptor type 1 S-glutathionylation

    J. Biol. Chem.

    (2006)
  • I. Dalle-Donne

    Actin S-glutathionylation: evidence against a thiol-disulphide exchange mechanism

    Free Radic. Biol. Med.

    (2003)
  • I. Dalle-Donne

    Reversible S-glutathionylation of Cys374 regulates actin filament formation by inducing structural changes in the actin molecule

    Free Radic. Biol. Med.

    (2003)
  • M. Demasi

    20 S proteasome from Saccharomyces cerevisiae is responsive to redox modifications and is S-glutathionylated

    J. Biol. Chem.

    (2003)
  • R. Gopalakrishna et al.

    Protein kinase C signaling and oxidative stress

    Free Radic. Biol. Med.

    (2000)
  • M.J. Penninckx

    An overview on glutathione in Saccharomyces versus non-conventional yeasts

    FEMS Yeast Res.

    (2002)
  • P. Eaton

    Protein thiol oxidation in health and disease: techniques for measuring disulfides and related modifications in complex protein mixtures

    Free Radic. Biol. Med.

    (2006)
  • A. Bindoli

    Thiol chemistry in peroxidase catalysis and redox signaling

    Antioxid. Redox Signal.

    (2008)
  • N. Clavreul

    S-glutathiolation by peroxynitrite of p21ras at cysteine-118 mediates its direct activation and downstream signaling in endothelial cells

    FASEB J.

    (2006)
  • N. Clavreul

    S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein

    Arterioscler. Thromb. Vasc. Biol.

    (2006)
  • J. Ying

    Cysteine-674 of the sarco/endoplasmic reticulum calcium ATPase is required for the inhibition of cell migration by nitric oxide

    Arterioscler. Thromb. Vasc. Biol.

    (2007)
  • M. Zheng

    Activation of the OxyR transcription factor by reversible disulfide bond formation

    Science

    (1998)
  • T. Adachi

    S-glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide

    Nat. Med.

    (2004)
  • S. Pan et al.

    Glutathiolation regulates tumor necrosis factor-(-induced caspase-3 cleavage and apoptosis: key role for glutaredoxin in the death pathway

    Circ. Res.

    (2007)
  • R. Bull

    Ischemia enhances activation by Ca2+ and redox modification of ryanodine receptor channels from rat brain cortex

    J. Neurosci.

    (2008)
  • G.M. Silva

    Role of glutaredoxin 2 and cytosolic thioredoxins in cysteinyl-based redox modification of the 20S proteasome

    FEBS J.

    (2008)
  • J.V. Cross et al.

    Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain

    Biochem. J.

    (2004)
  • F.C. Chen et al.

    Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin

    Am. J. Physiol. Cell Physiol.

    (2006)
  • Cited by (0)

    View full text