Abstract
Recent studies suggest that Peroxiredoxin 1 (Prdx1), in addition to its known H₂O₂-scavenging function, mediates cell signaling through redox-specific protein-protein interactions. Our data illustrate how Prdx1 specifically coordinates p38MAPK-induced signaling through regulating p38MAPKα phosphatases in an H₂O₂ dose-dependent manner. MAPK phosphatases (MKP-1 and/or MKP-5), which are known to dephosphorylate and deactivate the senescence-inducing MAPK p38α, belong to a group of redox-sensitive phosphatases (protein tyrosine phosphatases) characterized by a low pKa cysteine in their active sites. We found that Prdx1 bound to both MKP-1 and MKP-5, but dissociated from MKP-1 when the Prdx1 peroxidatic cysteine Cys52 was over-oxidized to sulfonic acid, which in turn resulted in MKP-1 oxidation-induced oligomerization and inactivity toward p38MAPKα. Conversely, over-oxidation of Prdx1-Cys52 was enhancing in the Prdx1:MKP-5 complex with increasing amounts of H₂O₂ concentrations and correlated with a protection from oxidation-induced oligomerization and inactivation of MKP-5 so that activation toward p38MAPK was maintained. Further examination of this Prdx1-specific mechanism in a model of reactive oxygen species-induced senescence of human breast epithelial cells revealed the specific activation of MKP-5, resulting in decreased p38MAPKα activity. Taken together, our data suggest that Prdx1 orchestrates redox signaling in an H₂O₂ dose-dependent manner through the oxidation status of its peroxidatic cysteine Cys52.
Highlights
A role for reactive oxygen species (ROS) in cell signaling has long been accepted, detailed evidence demonstrating their specific impact on signaling events is still lacking
Recent evidence suggests that Prdx[1] may be a ‘fine tuner’ of cellular H2O2 signaling by regulating the activity of binding partners[4] such as JNK,[5] c-Abl kinase[6] and as we have recently shown, the phosphatase PTEN.[7]
We demonstrate that Prdx[1] regulates p38MAPKa activity in senescence signaling by differentially modulating the activity of two p38MAPKa phosphatases, MAP kinase phosphatase 1 (MKP-1) and MKP-5
Summary
A role for reactive oxygen species (ROS) in cell signaling has long been accepted, detailed evidence demonstrating their specific impact on signaling events is still lacking. Cellular ROS impacts signaling through their localized accumulation, if we consider ROS as by-products of the electron transport chain in the mitochondria or activation of NADPH oxidases. This requires the local and timely availability of ROSscavenging enzymes at the time of ROS build-up, to protect proteins from oxidation-induced modifications affecting cell signaling. Over-oxidation of Prdx1’s Cys[52] renders the peroxidase inactive.[2,3,4] Recent evidence suggests that Prdx[1] may be a ‘fine tuner’ of cellular H2O2 signaling by regulating the activity of binding partners[4] such as JNK,[5] c-Abl kinase[6] and as we have recently shown, the phosphatase PTEN.[7]
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