Despite its toxicity, H(2)O(2) is produced as a signaling molecule that oxidizes critical cysteine residues of effectors such as protein tyrosine phosphatases in response to activation of cell surface receptors. It has remained unclear, however, how H(2)O(2) concentrations above the threshold required to modify effectors are achieved in the presence of the abundant detoxification enzymes peroxiredoxin (Prx) I and II. We now show that PrxI associated with membranes is transiently phosphorylated on tyrosine-194 and thereby inactivated both in cells stimulated via growth factor or immune receptors in vitro and in those at the margin of healing cutaneous wounds in mice. The localized inactivation of PrxI allows for the transient accumulation of H(2)O(2) around membranes, where signaling components are concentrated, while preventing the toxic accumulation of H(2)O(2) elsewhere. In contrast, PrxII was inactivated not by phosphorylation but rather by hyperoxidation of its catalytic cysteine during sustained oxidative stress.

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The active-site cysteine of peroxiredoxins is selectively oxidized to cysteine sulfinic acid during catalysis, which leads to inactivation of peroxidase activity. This oxidation was thought to be irreversible. However, by metabolic labeling of mammalian cells with 35 S, we show that the sulfinic form of peroxiredoxin I, produced during the exposure of cells to H 2 O 2 , is rapidly reduced to the catalytically active thiol form. The mammalian cells' ability to reduce protein sulfinic acid might serve as a mechanism to repair oxidatively damaged proteins or represent a new type of cyclic modification by which the function of various proteins is regulated.