Inactivation of a Peroxiredoxin by Hydrogen Peroxide Is Critical for Thioredoxin-Mediated Repair of Oxidized Proteins and Cell Survival

Alison M Day,Jonathon D Brown,Sarah R Taylor,Jonathan D Rand,Brian A Morgan,Elizabeth A Veal

doi:10.1016/j.molcel.2011.11.027

Alison M Day, Jonathon D Brown + Show 4 more

Open Access

https://doi.org/10.1016/j.molcel.2011.11.027

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Journal: Molecular Cell	Publication Date: Jan 12, 2012
Citations: 185	License type: cc-by

Affiliation: Newcastle University

Abstract

Eukaryotic 2-Cys peroxiredoxins (Prx) are abundant antioxidant enzymes whose thioredoxin peroxidase activity plays an important role in protecting against oxidative stress, aging, and cancer. Paradoxically, this thioredoxin peroxidase activity is highly sensitive to inactivation by peroxide-induced Prx hyperoxidation. However, any possible advantage in preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. Here we demonstrate that, in cells treated with hydrogen peroxide, the Prx Tpx1 is a major substrate for thioredoxin in the fission yeast Schizosaccharomyces pombe and, as such, competitively inhibits thioredoxin-mediated reduction of other oxidized proteins.Consequently, we reveal that the hyperoxidation of Tpx1 is critical to allow thioredoxin to act onother substrates ensuring repair of oxidized proteins and cell survival following exposure to toxiclevels of hydrogen peroxide. We conclude that the inactivation of the thioredoxin peroxidase activity of Prx is important to maintain thioredoxin activity and cell viability under oxidative stress conditions.

Highlights

The prevalence of oxygen and its intimate involvement in metabolism lead to unavoidable encounters between cells and reactive oxygen species (ROS) capable of irreversibly damaging vital cell components
Trx1 Is Required for the Reduction of Tpx1 Most eukaryotes contain multiple 2-Cys Prx proteins that are targeted to different cellular compartments, such as mitochondria and ER
Previous studies and our work suggest that Trx1 is the major cytosolic thioredoxin in S. pombe (Figure 2A) (Song and Roe, 2008)

Summary

Introduction

The prevalence of oxygen and its intimate involvement in metabolism lead to unavoidable encounters between cells and reactive oxygen species (ROS) capable of irreversibly damaging vital cell components. Cells have evolved multiple defenses against ROS including abundant antioxidant enzymes, such as peroxiredoxins which break down peroxides (Rhee and Woo, 2011). In response to rising levels of ROS, cells employ additional strategies to limit damage. Signaling pathways are activated to increase the levels of detoxification and repair enzymes or, alternatively, to initiate apoptosis to eliminate an irrevocably damaged cell. Despite these sophisticated defenses, ROS-induced damage has been implicated in many chronic diseases and in aging. There is great interest in developing strategies to augment cellular ROS defenses

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