Hyperoxia Regulates The Degradation Of The Circadian Protein Rev-Erbα: Implications For Cytoprotection

Peroxiredoxins (Prx) are abundant, multifunctional antioxidant proteins with important roles in protecting against oxidative stress, ageing and cancer. The thioredoxin peroxidase activity of eukaryotic typical 2Cys Prx detoxifies hydrogen peroxide, but, enigmatically, is highly sensitive to inactivation by peroxide-induced hyperoxidation of a catalytic cysteine residue. It has been proposed that hyperoxidation might allow hydrogen peroxide to act as a signal and/or promote an alternative activity of Prx as a chaperone. However, any advantage to be gained by inhibiting the thioredoxin peroxidase activity and preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. The fission yeast Schizosaccharomyces pombe contains a single 2-Cys Prx, Tpx1, which we have identified as the major substrate for the thioredoxin Trx1. Accordingly, we find Tpx1 competitively inhibits the activity of Trx1 towards other substrates, such as the AP-1-like transcription factor, Pap1, and the methionine sulphoxide reductase, MsrA. Consequently, we demonstrate that the oxidative inactivation of the thioredoxin peroxidase activity of Tpx1 (i) prevents hydrogen peroxide-induced oxidation of thioredoxin, Pap1 and MsrA, (ii) allows repair of oxidative protein damage, and (iii) is important for maintaining cell viability following exposure to toxic levels of hydrogen peroxide. In summary, we propose that an important function for the reversible hyperoxidation of 2-Cys Prx is to regulate the redox status of thioredoxin and thus thioredoxinmediated signalling and repair processes. We will present data to support this conclusion including data revealing the important impact of these mechanisms for the activation of a p38-related MAPK by oxidative stress.