Both Thioredoxin 2 and Glutaredoxin 2 Contribute to the Reduction of the Mitochondrial 2-Cys Peroxiredoxin Prx3

Hanschmann, Eva-Maria; Lönn, Maria; Schütte, Lena Dorothee; Funke, Maria; Godoy, José R.; Eitner, Susanne; Hudemann, Christoph; Lillig, Christopher Horst

doi:10.1074/jbc.m110.185827

Cited by 100 publications

(86 citation statements)

References 41 publications

(39 reference statements)

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“…Others have detected glutathionylated Prxs in proteomic screens and observed secretion from cells under oxidative and inflammatory stress (27,28). Reduction of Prx3 by Grx2 has also been observed, but in this case, the disulfide was reduced directly without involving a glutathionylated intermediate (6). The ease of active site glutathionylation, as shown here for Prx2 and which may apply to other 2-Cys Prxs, has not previously been recognized.…”

Section: Table 4 Detection Of Glutathionylated Prx2 In Erythrocytes Fmentioning

confidence: 71%

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

Peskin

Pace

Behring

et al. 2016

Journal of Biological Chemistry

100

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Peroxiredoxin 2 (Prx2) is a thiol protein that functions as an antioxidant, regulator of cellular peroxide concentrations, and sensor of redox signals. Its redox cycle is widely accepted to involve oxidation by a peroxide and reduction by thioredoxin/ thioredoxin reductase. Interactions of Prx2 with other thiols are not well characterized. Here we show that the active site Cys residues of Prx2 form stable mixed disulfides with glutathione (GSH). Glutathionylation was reversed by glutaredoxin 1 (Grx1), and GSH plus Grx1 was able to support the peroxidase activity of Prx2. Prx2 became glutathionylated when its disulfide was incubated with GSH and when the reduced protein was treated with H 2 O 2 and GSH. The latter reaction occurred via the sulfenic acid, which reacted sufficiently rapidly (k ‫؍‬ 500 M ؊1 s ؊1 ) for physiological concentrations of GSH to inhibit Prx disulfide formation and protect against hyperoxidation to the sulfinic acid. Glutathionylated Prx2 was detected in erythrocytes from Grx1 knock-out mice after peroxide challenge. We conclude that Prx2 glutathionylation is a favorable reaction that can occur in cells under oxidative stress and may have a role in redox signaling. GSH/Grx1 provide an alternative mechanism to thioredoxin and thioredoxin reductase for Prx2 recycling.

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Section: Table 4 Detection Of Glutathionylated Prx2 In Erythrocytes Fmentioning

confidence: 71%

“…The main reducing systems are thioredoxin/thioredoxin reductase (Trx/ TrxR) 2 and glutaredoxin (Grx)/GSH, both of which ultimately depend on NADPH (2,5). Although these have different specificities and were initially regarded as acting in parallel, it is becoming apparent that the two systems interact (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

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

Peskin

Pace

Behring

et al. 2016

Journal of Biological Chemistry

100

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“…7, reaction 6). To note, glutaredoxins from different cellular sources have been reported to be involved in homologous Prxs reduction and both monothiolic and dithiolic mechanisms have been proposed (37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Mycothiol/Mycoredoxin 1-dependent Reduction of the Peroxiredoxin AhpE from Mycobacterium tuberculosis

Hugo

Laer

Reyes

et al. 2014

Journal of Biological Chemistry

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Background: Mycothiol, the major low-molecular weight thiol of Mycobacterium tuberculosis, is important for peroxide detoxification and virulence. Results: Mycothiol, together with mycoredoxin-1, a glutaredoxin-like protein, reduces the one-cysteine peroxiredoxin AhpE from the bacterium. Conclusion: Mycobacterium tuberculosis AhpE is a mycothiol/mycoredoxin-1-dependent peroxidase. Significance: Our results provide the first molecular link between a thiol-dependent peroxidase and the mycothiol/mycoredoxin-1 pathway in Mycobacteria.

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“…Rat recombinant IFN-γ and human recombinant TNF-α were obtained from R&D Systems. Human recombinant PRDX2 was expressed in E. coli as described elsewhere (36) and cleared from LPS contamination using Detoxi-Gel columns (Pierce). Purified PRDX2 was then tested for LPS contamination using the limulus amoebocyte lysate assay (Pyrogent Plus; Lonza).…”

Section: Methodsmentioning

confidence: 99%

Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal

Salzano

Checconi

Hanschmann³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

294

231

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The mechanism by which oxidative stress induces inflammation and vice versa is unclear but is of great importance, being apparently linked to many chronic inflammatory diseases. We show here that inflammatory stimuli induce release of oxidized peroxiredoxin-2 (PRDX2), a ubiquitous redox-active intracellular enzyme. Once released, the extracellular PRDX2 acts as a redoxdependent inflammatory mediator, triggering macrophages to produce and release TNF-α. The oxidative coupling of glutathione (GSH) to PRDX2 cysteine residues (i.e., protein glutathionylation) occurs before or during PRDX2 release, a process central to the regulation of immunity. We identified PRDX2 among the glutathionylated proteins released in vitro by LPS-stimulated macrophages using mass spectrometry proteomic methods. Consistent with being part of an inflammatory cascade, we find that PRDX2 then induces TNF-α release. Unlike classical inflammatory cytokines, PRDX2 release does not reflect LPS-mediated induction of mRNA or protein synthesis; instead, PRDX2 is constitutively present in macrophages, mainly in the reduced form, and is released in the oxidized form on LPS stimulation. Release of PRDX2 is also observed in human embryonic kidney cells treated with TNF-α. Importantly, the PRDX2 substrate thioredoxin (TRX) is also released along with PRDX2, enabling an oxidative cascade that can alter the -SH status of surface proteins and thereby facilitate activation via cytokine and Toll-like receptors. Thus, our findings suggest a model in which the release of PRDX2 and TRX from macrophages can modify the redox status of cell surface receptors and enable induction of inflammatory responses. This pathway warrants further exploration as a potential novel therapeutic target for chronic inflammatory diseases.cysteine oxidation | thiol oxidation | redox proteomics

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Both Thioredoxin 2 and Glutaredoxin 2 Contribute to the Reduction of the Mitochondrial 2-Cys Peroxiredoxin Prx3

Cited by 100 publications

References 41 publications

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

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

Mycothiol/Mycoredoxin 1-dependent Reduction of the Peroxiredoxin AhpE from Mycobacterium tuberculosis

Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal

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