Sulfiredoxin: a potential therapeutic agent?

doi:10.1016/j.biopha.2005.07.003

Biomedicine & Pharmacotherapy

Volume 59, Issue 7, August 2005, Pages 374-379

https://doi.org/10.1016/j.biopha.2005.07.003 Get rights and content

Abstract

The importance of antioxidants in maintaining homeostasis has long been accepted and includes antioxidant proteins such as, peroxiredoxin (Prx), superoxide dismutase and glutathione S transferases. Sulfiredoxin (Srx) is a recently identified antioxidant protein with a role in signaling through catalytic reduction of oxidative modifications. It was first characterized for its regulation of Prx(s) through reduction of the conserved cysteine from sulfinic to sulfenic acid, thereby impacting the role of Prx in regulation of downstream transcription factors and kinase signaling pathways. Furthermore, the reduction of sulfinic to sulfenic acid prevents further oxidation of the conserved cysteine residue to sulfonic acid, the end result of which is degradation. Srx also has a role in the reduction of glutathionylation a post-translational, oxidative modification that occurs on numerous proteins and has been implicated in a wide variety of pathologies, including Parkinson’s disease. The regulation of glutathionylation/deglutathionylation (or thiol switch) has been likened to phosphorylation/dephosphorylation, another post-translational modification involved in the regulation of signaling pathways. Unlike, the reduction of Prx over-oxidation, Srx-dependent deglutathionylation appears to be non-specific. Deglutathionylation of multiple proteins has been observed both in vitro and in vivo in response to oxidative and/or nitrosative stress. This review discusses Srx as a novel antioxidant, and focuses on its potential role in the regulation of glutathionylation/deglutathionylation pathways, that have been implicated in a growing number of disease states.

Section snippets

General introduction

Cells have evolved an intricate network of antioxidant molecules and proteins that are required to maintain homeostasis. Reactive oxygen species (ROS) are generated exogenously by environmental agents or endogenously as a consequence of normal cellular metabolic processes including, respiration. When ROS levels exceed the antioxidant capacity of cells, oxidative stress (OS) results. The toxicity of ROS is due to their ability to damage a large number of cellular constituents, of which

Srx, a novel antioxidant protein

OSR is a term that is used to describe the signaling events that occur when the intracellular OS is higher than the antioxidant capacity of the cell. Srx was first identified in Saccharomyces cerevisiae and was found to be involved in the OSR [4]. Srx is not only induced in response to treatment with H₂O₂ but deletion of the gene leads to a decreased resistance to H₂O₂. Insight into its mechanism of action was clarified when Srx was identified as a binding partner to the yeast peroxiredoxin

Glutathionylation as a post-translational modification

GSH is a critical antioxidant in the cell and its' conjugation to electrophilic compounds is essential to the detoxification pathway. We are now beginning to realize the potentially major role that GSH plays in post-translational modifications that alter cellular response to oxidative and nitrosative stress. It is not surprising that GSH is present in millimolar concentrations in the cell. In fact, the ratio of the reduced GSH pool to glutathione disulfide (GSSG) is a redox sensor and used to

Deglutathionylation as a mechanism of cellular stress regulation

Reversibility of post-translational modifications is a requisite for cellular signaling. Deglutathionylation is the removal of the GSH moiety from proteins and can occur when the environment becomes more reducing in an enzyme-dependent or -independent manner. To date, a limited number of proteins have been identified that are involved in deglutathionylation. Grx is a well-characterized protein known to be involved in both the oxidative glutathionylation and the reductive deglutathionylation

Oxidative/nitrosative stress and disease

Formation of ROS and RNS is not only the result of an exogenous insult, but a consequence of normal cellular metabolism. It is the tight regulation of these processes within the cell that allows maintenance of homeostasis and consequently a limit to the amount of damage caused by these ROS/RNS. Dysregulation leads to an accumulation of ROS/RNS resulting in cellular damage. Unfortunately however, many diseases are associated with an increase in oxidative/nitrosative damage and aging itself is

Concluding remarks

Glutathionylation is emerging as an important post-translational modification that influences a large number of proteins. The growing number of disease states that are correlated with increased glutathionylation of specific proteins highlights the need to understand the underlying mechanisms involved in the regulation of the glutathionylation and deglutathionylation pathways. The identification of Srx and its role as a novel antioxidant protein specifically involved in the deglutathionylation

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Hyperglycemia-induced podocyte injury plays a vital role in the development of diabetic nephropathy. Sulfiredoxin-1 (Srxn1) is emerging as a cytoprotective protein that protects from various insults in a wide range of cell types. However, whether Srxn1 is involved in regulating hyperglycemia-induced podocyte injury and participates in diabetic nephropathy remains unknown. In the present study, we aimed to explore the potential role of Srxn1 in regulating high glucose (HG)-induced apoptosis and oxidative stress of podocytes in vitro. Results demonstrated that Srxn1 was induced in HG-stimulated podocytes. The depletion of Srxn1 by Srxn1 siRNA-mediated gene silencing significantly exacerbated HG-induced apoptosis and the production of reactive oxygen species (ROS), while Srxn1 overexpression attenuated HG-induced apoptosis and ROS production. In-depth molecular mechanism research revealed that Srxn1 overexpression promoted the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and reinforced antioxidant response element (ARE)-mediated transcription activity. Moreover, results confirmed that Srxn1 increased the activation of Nrf2/ARE signaling associated with inactivating glycogen synthase kinase (GSK)-3β. Notably, the inhibition of GSK-3β significantly reversed Srxn1 silencing-induced adverse effects in HG-treated cells, while the knockdown of Nrf2 abrogated the Srxn1-mediated protective effect against HG-induced podocyte injury. Taken together, our results demonstrated that Srxn1 protects podocytes from HG-induced injury by promoting the activation of Nrf2/ARE signaling associated with inactivating GSK-3β, indicating a potential role of Srxn1 in diabetic nephropathy. Our study suggests that Srxn1 may serve as a potential target for kidney protection.
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Citation Excerpt :
The present study is the first to undertake a comprehensive analysis of SRXN1 function in cardiac progenitor cells. SRXN1 has been recognized as an endogenous antioxidant that protects against brain tissue damage in Parkinson's disease [37]. Recent studies have confirmed the critical role of SRXN1 in regulating oxidative stress-triggered cell death in neuronal cells [20,38] and cardiomyocytes [24].
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Dossier : Antioxidants in the prevention of human diseasesSulfiredoxin: a potential therapeutic agent?

Abstract

Section snippets

General introduction

Srx, a novel antioxidant protein

Glutathionylation as a post-translational modification

Deglutathionylation as a mechanism of cellular stress regulation

Oxidative/nitrosative stress and disease

Concluding remarks

Neurosci. Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Ageing Res. Rev.

Methods Enzymol.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Regulation of JNK signaling by GSTp

EMBO J.

Regulation of PTP1B via glutathionylation of the active site cysteine 215

Biochemistry

Dossier : Antioxidants in the prevention of human diseases
Sulfiredoxin: a potential therapeutic agent?