Abstract
Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage.
Highlights
Reactive oxygen species (ROS) generated by the partial reduction of oxygen during aerobic metabolism, immune cell attack or London, London E15 4LZ, UK.following exposure to radiation can cause lethal levels of cell damage
We have shown that the role of the thioredoxin peroxidase activity of Tpx1 in hydrogen peroxide (H2O2)-induced Pap1 activation is to competitively inhibit the reduction of the active, oxidized form of Pap1 by the thioredoxin-like protein, thioredoxin-like protein 1 (Txl1) [11]
To test whether thioredoxin-dependent processes are important for inhibiting increases in intracellular H2O2 in cells exposed to r 150 μM H2O2, we examined how extracellular H2O2 treatment affected intracellular H2O2 concentration in mutant S. pombe lacking, or ectopically expressing additional thioredoxin and/or
Summary
Reactive oxygen species (ROS) generated by the partial reduction of oxygen during aerobic metabolism, immune cell attack or London, London E15 4LZ, UK. Following exposure to radiation can cause lethal levels of cell damage. Altered redox homeostasis and increased oxidative cell damage are associated with the development of many common diseases, including cancer, diabetes, cardiovascular and neurodegenerative diseases. There is increasing evidence that low levels of ROS can have beneficial effects; acting as signaling molecules to regulate diverse biological processes (for a review see [1]). There is considerable interest in understanding how cells optimize ROS defenses to provide adequate protection without compromising ROS-signaling functions. We have developed and used a mathematical model as a tool to understand what governs how cells respond to increases in hydrogen peroxide (H2O2)
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