A Peroxiredoxin Promotes H2O2 Signaling and Oxidative Stress Resistance by Oxidizing a Thioredoxin Family Protein

• The thioredoxin-like protein Txl1 is oxidized in response to H2O2
• The thioredoxin peroxidase activity of the Prx Tpx1 is required for oxidation of Txl1
• The AP-1-like transcription factor Pap1 is an in vivo substrate for Txl1
• Tpx1’s thioredoxin peroxidase activity provides H2O2 resistance by regulating Txl1

SummaryH2O2 can cause oxidative damage associated with age-related diseases such as diabetes and cancer but is also used to initiate diverse responses, including increased antioxidant gene expression. Despite significant interest, H2O2-signaling mechanisms remain poorly understood. Here, we present a mechanism for the propagation of an H2O2 signal that is vital for the adaptation of the model yeast, Schizosaccharomyces pombe, to oxidative stress. Peroxiredoxins are abundant peroxidases with conserved antiaging and anticancer activities. Remarkably, we find that the only essential function for the thioredoxin peroxidase activity of the Prx Tpx1(hPrx1/2) in resistance to H2O2 is to inhibit a conserved thioredoxin family protein Txl1(hTxnl1/TRP32). Thioredoxins regulate many enzymes and signaling proteins. Thus, our discovery that a Prx amplifies an H2O2 signal by driving the oxidation of a thioredoxin-like protein has important implications, both for Prx function in oxidative stress resistance and for responses to H2O2.

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