A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation.

Hydrogen peroxide (H ₂ O ₂ ) acts as a signaling messenger by triggering the reversible oxidation of redox-regulated proteins. It remains unclear how proteins can be oxidized by signaling levels of H ₂ O ₂ in the presence of peroxiredoxins, which are highly efficient peroxide scavengers. Here we show that the rapid formation of disulfide bonds in cytosolic proteins is enabled, rather than competed, by cytosolic 2-Cys peroxiredoxins. Under the conditions tested, the combined deletion or depletion of cytosolic peroxiredoxins broadly frustrated H ₂ O ₂ -dependent protein thiol oxidation, which is the exact opposite of what would be predicted based on the assumption that H ₂ O ₂ oxidizes proteins directly. We find that peroxiredoxins enable rapid and sensitive protein thiol oxidation by relaying H ₂ O ₂ -derived oxidizing equivalents to other proteins. Although these findings do not rule out the existence of Prx-independent H ₂ O ₂ signaling mechanisms, they suggest a broader role for peroxiredoxins as sensors and transmitters of H ₂ O ₂ signals than hitherto recognized.