Graded Response of the Multifunctional 2-Cysteine Peroxiredoxin, CgPrx, to Increasing Levels of Hydrogen Peroxide in Corynebacterium glutamicum

Aims: Eukaryotic typical 2-cysteine (Cys) peroxiredoxins (Prxs) are multifunctional proteins subjected to complex regulation and play important roles in oxidative stress resistance, hydrogen peroxide (H 2 O 2 ) signaling modulation, aging, and cancer, but the information on the biochemical functions and regulation mechanisms of prokaryotic atypical 2-Cys Prxs is largely lacking. Results: In this study, we show that at low peroxide concentrations, the atypical 2-Cys Prx in Corynebacterium glutamicum (CgPrx) mainly exists as monomers and displays thioredoxin (Trx)-dependent peroxidase activity. Moderate oxidative stress causes reversible S -mycothiolation of the H 2 O 2 -sensing Cys63 residue, which keeps CgPrx exclusively in dimer form with neither peroxidase nor chaperone activity. Then, the increased levels of H 2 O 2 could act as a messenger to oxidize the redox-sensitive regulator hydrogen peroxide-inducible gene activator, leading to activation of expression of the more efficient mycothiol peroxidase and catalase to eliminate excessive peroxide. If oxidative stress is too severe, the H 2 O 2 -sensing Cys63 becomes hyperoxidized to sulfonic acid, which irreversibly inactivates the peroxidase activity, and most of CgPrx will be converted to multimeric chaperones for salvage of damaged proteins. Innovation: We demonstrate for the first time that atypical 2-Cys CgPrx acts as both a Trx-dependent peroxidase and a molecular chaperone and plays a regulatory role in modulating the peroxide-mediated signaling cascades. Conclusion: These results reveal that CgPrx functions as a multifunctional protein crucial for adapting appropriate responses to different levels of oxidative challenge in C. glutamicum . Antioxid. Redox Signal. 26, 1–14.