Inactivation of Peroxiredoxin I by Phosphorylation Allows Localized H2O2 Accumulation for Cell Signaling

Abstract

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.

Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

“…Inactivation of Prxs occurs by overoxidation of the active site cysteine to sulfinic acid, and this permits accumulated H 2 O 2 to then react with its targets (17,19,44). More recently, a report proposed that Prx2 is inactivated by hyperoxidation of its catalytic cysteine, whereas Prx1 is inactivated locally by phosphorylation but by hyperoxidation during H 2 O 2 signaling at the cell membrane (20,45). However, because Trx1 is an efficient electron donor to Prx1, Prx1 is not supposed to be inactive if Trx1 is still active.…”

Peroxiredoxin Functions as a Peroxidase and a Regulator and Sensor of Local Peroxides

“…As described below, certain Prx enzymes also function as local regulators of H 2 O 2 , which serves as an intracellular messenger. The tumor suppressor function of Prx I was attributed to such regulation of H 2 O 2 (40,41).…”

Oxidative Stress: Antagonistic Signaling for Acclimation or Cell Death?

“…H 2 O 2 accumulation is facilitated by transient inactivation of H 2 O 2 -scavenging peroxiredoxins by phosphorylation. This occurs within subcellular microdomains, and the accumulated H 2 O 2 , for a short period, inhibits signalingassociated protein Tyr phosphatases (Woo et al, 2010). In plants, the best described source of plasma membrane-associated NADPH oxidase is that encoded by the respiratory burst oxidases (Rbohs) homologous to the gp91 phox subunit of mammalian neutrophil NADPH oxidases (Sagi and Fluhr, 2006).…”