The Conundrum of Hydrogen Peroxide Signaling and the Emerging Role of Peroxiredoxins as Redox Relay Hubs.

Significance: Hydrogen peroxide (H2O2) is known to act as a messenger in signal transduction. How H2O2 leads to selective and efficient oxidation of specific thiols on specific signaling proteins remains one of the most important open questions in redox biology. Recent Advances: Increasing evidence implicates thiol peroxidases as mediators of protein thiol oxidation. Recently, this evidence has been extended to include the peroxiredoxins (Prxs). Prxs are exceptionally sensitive to H2O2, abundantly expressed and capture most of the H2O2 that is generated inside cells. Critical Issues: The overall prevalence and importance of Prx-based redox signaling relays are still unknown. The same is true for alternative mechanisms of redox signaling. Future Directions: It will be important to clarify the relative contributions of Prx-mediated and direct thiol oxidation to H2O2 signaling. Many questions relating to Prx-based redox relays remain to be answered, including theirmechanism, structural organization, and the potential role of adaptor proteins.