Trends in Biochemical Sciences
ReviewProtein S-glutathionylation: a regulatory device from bacteria to humans
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
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