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

Peskin, Alexander V.; Pace, Paul E.; Behring, Jessica B.; Paton, Louise N.; Soethoudt, Marjolein; Bachschmid, Markus; Winterbourn, Christine C.

doi:10.1074/jbc.m115.692798

Cited by 104 publications

(93 citation statements)

References 40 publications

(54 reference statements)

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“…Fig. 6) [15, 16, 55-57]. In addition, several putative targets for glutathionylation, including Rnr1 and Leu1, were cross-linked to GSH upon DVSF treatment (Supp.…”

Section: Resultsmentioning

confidence: 99%

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Allan

Loberg

Chepngeno

et al. 2016

Free Radical Biology and Medicine

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A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.

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“…Fig. 6) [15, 16, 55-57]. In addition, several putative targets for glutathionylation, including Rnr1 and Leu1, were cross-linked to GSH upon DVSF treatment (Supp.…”

Section: Resultsmentioning

confidence: 99%

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Allan

Loberg

Chepngeno

et al. 2016

Free Radical Biology and Medicine

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“…Other important defensive mechanisms and mediators of redox signaling are represented by the peroxiredoxin, the thioredoxin (TRX) and the glutathione/glutaredoxin systems. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Due to intrinsic differences in the half-life, stability, chemical reactivity, cellular context, site and source of their generation (exogenous or endogenous), ROS can interact and modify different classes of biological macromolecules including DNA, lipids and proteins. 31, 32, 33, 34, 35, 36, 37 The tight regulation of ROS production and detoxification over time and space represents the basis for the maintenance of an appropriate redox homeostasis and redox signaling events.…”

Section: Ros Homeostasis and Redox Cofactors In Normal And Tumor Cellsmentioning

confidence: 99%

ROS homeostasis and metabolism: a dangerous liason in cancer cells

2016

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Tumor cells harbor genetic alterations that promote a continuous and elevated production of reactive oxygen species. Whereas such oxidative stress conditions would be harmful to normal cells, they facilitate tumor growth in multiple ways by causing DNA damage and genomic instability, and ultimately, by reprogramming cancer cell metabolism. This review outlines the metabolic-dependent mechanisms that tumors engage in when faced with oxidative stress conditions that are critical for cancer progression by producing redox cofactors. In particular, we describe how the mitochondria has a key role in regulating the interplay between redox homeostasis and metabolism within tumor cells. Last, we will discuss the potential therapeutic use of agents that directly or indirectly block metabolism.

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“…[33,34,28,35,2]. Second, because these Prx forms can be glutathionylated (PSSG) [56,57], PSSG might in turn glutathionylate redox targets either directly or mediated by glutaredoxin, as suggested in ref. [14].…”

Section: Discussionmentioning

confidence: 97%

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

Travasso

Aidos

Abranches

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THydrogen peroxide (H 2 O 2 ) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H 2 O 2 -reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H 2 O 2 signaling. The results show that at H 2 O 2 supply rates commensurate with mitogenic signaling a H 2 O 2 concentration gradient with a length scale of a few tenths of μm is established. Even near the supply sites H 2 O 2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H 2 O 2 supply able to drastically increase the local H 2 O 2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H 2 O 2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 μm from the H 2 O 2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H 2 O 2 for the oxidation of redox targets. Altogether, these results suggest that H 2 O 2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H 2 O 2 supply sites and these forms in turn oxidize the redox targets near these sites.

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

Cited by 104 publications

References 40 publications

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

ROS homeostasis and metabolism: a dangerous liason in cancer cells

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

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