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Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling



Hydrogen peroxide (H2O2) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H2O2 (kapp 1–10 M−1 s−1), can be specifically and efficiently oxidized by H2O2. Moreover, cellular thiol peroxidases, which are highly abundant and efficient H2O2 scavengers, should effectively eliminate virtually all of the H2O2 produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H2O2-reactive proteins in the cell (kapp 107–108 M−1 s−1), acts as a H2O2 signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.

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Figure 1: Prx2 forms disulfide exchange intermediates with STAT3.
Figure 2: Prx2 oxidizes STAT3.
Figure 3: Prx2 targets the DNA binding and trans-activating domains of STAT3.
Figure 4: Independent oxidation pathways lead to covalent dimers and tetramers.
Figure 5: IL6-type cytokines induce Prx2 and STAT3 oxidation.
Figure 6: Generalized model of peroxidase-mediated redox signaling.

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T.P.D. is supported by the Deutsche Forschungsgemeinschaft (SFB 1036, SFB 938 and SPP 1710). M.C.S. was supported by a PhD fellowship from the Boehringer Ingelheim Fonds. We thank B. Morgan and R. Jarvis for critical and helpful comments on the manuscript.

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Authors and Affiliations



M.C.S. and T.P.D. conceived the project, designed the experiments, analyzed the data and wrote the manuscript. M.C.S. performed most experiments; W.L. generated and analyzed cysteine mutants; S.S. performed luciferase reporter assays; S.S. and D.T. analyzed cytokine-induced protein oxidation; M.O. performed experiments relating to the role of thioredoxin; T.R. and A.N.D.S. performed MS experiments.

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Correspondence to Tobias P Dick.

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The authors declare no competing financial interests.

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Sobotta, M., Liou, W., Stöcker, S. et al. Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling. Nat Chem Biol 11, 64–70 (2015).

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