Protein Glutathionylation in the Regulation of Peroxiredoxins: A Family of Thiol-Specific Peroxidases That Function As Antioxidants, Molecular Chaperones, and Signal Modulators

School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 11/2011; 16(6):506-23. DOI: 10.1089/ars.2011.4260
Source: PubMed


Reversible protein glutathionylation plays an important role in cellular regulation, signaling transduction, and antioxidant defense. This redox-sensitive mechanism is involved in regulating the functions of peroxiredoxins (Prxs), a family of ubiquitously expressed thiol-specific peroxidase enzymes. Glutathionylation of certain Prxs at their active-site cysteines not only provides reducing equivalents to support their peroxidase activity but also protects Prxs from irreversible hyperoxidation. Typical 2-Cys Prx also functions as a molecular chaperone when it exists as a decamer and/or higher molecular weight complexes. The hyperoxidized sulfinic derivative of 2-Cys Prx is reactivated by sulfiredoxin (Srx). In this review, the roles of glutathionylation in the regulation of Prxs are discussed with respect to their molecular structure and functions as antioxidants, molecular chaperones, and signal modulators. RECENT ADVANCES: Recent findings reveal that glutathionylation regulates the quaternary structure of Prx. Glutathionylation of Prx I at Cys(83) converts the decameric Prx to its dimers with the loss of chaperone activity. The findings that dimer/oligomer structure specific Prx I binding proteins, e.g., phosphatase and tensin homolog (PTEN) and mammalian Ste20-like kinase-1 (MST1), regulate cell cycle and apoptosis, respectively, suggest a possible link between glutathionylation and those signaling pathways.
Knowing how glutathionylation affects the interaction between Prx I and its nearly 20 known interacting proteins, e.g., PTEN and MST1 kinase, would reveal new insights on the physiological functions of Prx.
In vitro studies reveal that Prx oligomerization is linked to its functional changes. However, in vivo dynamics, including the effect by glutathionylation, and its physiological significance remain to be investigated.

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    • "This is also true for the relevance of other Trx-and Grx-isoforms. They can either serve as reductants for Prx, or depend on GSH, which is not only the electron donor for some GPx but also a modulator of Prx function (Chae et al., 2012). "
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    ABSTRACT: Abstract The spatiotemporal modification of specific cysteinyl residues in proteins has emerged as a novel concept in signal transduction. Such modifications alter the redox state of the cysteinyl thiol group with implications for the structure and biological function of the protein. Regulatory cysteines are therefore classified as 'thiol switches'. In this review we emphasize the relevance of enzymes for specific and efficient redox sensing, evaluate prerequisites and general properties of redox switches, and highlight mechanistic principles for toggling thiol switches. Moreover, we provide an overview of potential mechanisms for the initial formation of regulatory disulfide bonds. In brief, we address the three basic questions (i) what defines a thiol switch, (ii) which parameters confer signal specificity, and (iii) how are thiol switches oxidized.
    Biological Chemistry 01/2015; DOI:10.1515/hsz-2014-0280 · 3.27 Impact Factor
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    • "The mammalian peroxiredoxin (Prx) family which consists of six proteins is H2O2-scavenging enzymes present in procaryotic and eucaryotic cells [11]–[13]. Prx-I belongs to typical-2-Cys and is the most abundant and ubiquitously distributed isoform of PRDX [14], [15], which has been closely interrelated with cell proliferation and differentiation, intracellular redox signaling, and apoptosis [16]–[19]. Prx-I is highly expressed in solid organs and in tissues of some cancers [20]–, and is also positively associated with the recurrence and progression rates of bladder cancer [24], [25]. "
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    ABSTRACT: In order to understand the molecular mechanisms of Bifidobacterium infantis thymidine kinase/nucleoside analogue ganciclovir (BI-TK/GCV) treatment system which was proven to exhibit sustainable anti-tumor growth activity and induce apoptosis in bladder cancer, a proteomic approach of isobaric tags for relative and absolute quantification (iTRAQ), followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used. 192 down-regulated and 210 up-regulated proteins were identified after treatment with BI-TK/GCV system in Sprague-Dawley (SD) rats. Western blot analysis and immunohistochemistry analysis confirmed that Peroxiredoxin-I (Prx-I) was significantly down-regulated in bladder cancer after treatment. Prx-I silencing by transfection of Prx-I shRNA significantly suppressed growth, promoted apoptosis and regulated the cell cycle in T24 cells and reduced the phospho-NF-κB p50 and p65 protein expression which revealed the links between Prx-I and NF-κB pathway implied by Ingenuity pathway analysis (IPA). These findings yield new insights into the therapy of bladder cancer, revealing Prx-I as a new therapeutic target and indicating BI-TK/GCV system as a prospective therapy by down-regulation of Prx-I through NF-κB signaling pathway.
    PLoS ONE 06/2014; 9(6):e98764. DOI:10.1371/journal.pone.0098764 · 3.23 Impact Factor
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    • "Oxidative stress is a common contributor to disease and tissue injury, making the maintenance of intracellular redox homeostasis a decisive determinant for cell death or survival. Peroxiredoxins are components of a ubiquitous thioredoxin-dependent antioxidant defense system that catalyzes the inactivation of reactive oxygen species (ROS) or their progenitors, including hydrogen peroxide (H2O2) and peroxynitrite (ONOO−), as well as the reduction of protein sulfhydryl groups [1], [2]. The six known isoforms of the family of mammalian peroxiredoxins exhibit cell-specific distribution patterns and are localized to different cellular compartments. "
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    ABSTRACT: This study delineates the role of peroxiredoxin 3 (Prx3) in hair cell death induced by several etiologies of acquired hearing loss (noise trauma, aminoglycoside treatment, age). In vivo, Prx3 transiently increased in mouse cochlear hair cells after traumatic noise exposure, kanamycin treatment, or with progressing age before any cell loss occurred; when Prx3 declined, hair cell loss began. Maintenance of high Prx3 levels via treatment with the radical scavenger 2,3-dihydroxybenzoate prevented kanamycin-induced hair cell death. Conversely, reducing Prx3 levels with Prx3 siRNA increased the severity of noise-induced trauma. In mouse organ of Corti explants, reactive oxygen species and levels of Prx3 mRNA and protein increased concomitantly at early times of drug challenge. When Prx3 levels declined after prolonged treatment, hair cells began to die. The radical scavenger p-phenylenediamine maintained Prx3 levels and attenuated gentamicin-induced hair cell death. Our results suggest that Prx3 is up-regulated in response to oxidative stress and that maintenance of Prx3 levels in hair cells is a critical factor in their susceptibility to acquired hearing loss.
    PLoS ONE 04/2013; 8(4):e61999. DOI:10.1371/journal.pone.0061999 · 3.23 Impact Factor
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