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A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation

Nature Chemical Biology volume 14, pages 148–155 (2018)Cite this article

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Abstract

Hydrogen peroxide (H2O2) acts as a signaling messenger by triggering the reversible oxidation of redox-regulated proteins. It remains unclear how proteins can be oxidized by signaling levels of H2O2 in the presence of peroxiredoxins, which are highly efficient peroxide scavengers. Here we show that the rapid formation of disulfide bonds in cytosolic proteins is enabled, rather than competed, by cytosolic 2-Cys peroxiredoxins. Under the conditions tested, the combined deletion or depletion of cytosolic peroxiredoxins broadly frustrated H2O2-dependent protein thiol oxidation, which is the exact opposite of what would be predicted based on the assumption that H2O2 oxidizes proteins directly. We find that peroxiredoxins enable rapid and sensitive protein thiol oxidation by relaying H2O2-derived oxidizing equivalents to other proteins. Although these findings do not rule out the existence of Prx-independent H2O2 signaling mechanisms, they suggest a broader role for peroxiredoxins as sensors and transmitters of H2O2 signals than hitherto recognized.

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Figure 1: H2O2-induced cytosolic protein thiol oxidation depends on cytosolic peroxiredoxins.
Figure 2: Trx1 and TrxR1 are not required for transmission of oxidative equivalents to cytosolic proteins.
Figure 3: Upon H2O2 exposure, peroxiredoxins form transient disulfide exchange intermediates with other proteins.
Figure 4: Oxidation of individual redox-regulated proteins depends on the presence of Prxs.

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Acknowledgements

We thank G. Kuntz for general technical assistance. We thank S. Merker and R. Hardt for technical assistance with mass spectrometry. We thank B. Jovanovic and G. Stöcklin for technical advice. We acknowledge support by the Deutsche Forschungsgemeinschaft (SFB1036 to T.P.D. and T.R.) and by the European Research Council (742039 to T.P.D.).

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Authors and Affiliations

  1. Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Sarah Stöcker, Michael Maurer & Tobias P Dick

  2. Core Facility for Mass Spectrometry and Proteomics, DKFZ-ZMBH Alliance, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg, Germany

    Thomas Ruppert

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T.P.D. and S.S. designed the project and wrote the paper. S.S. performed the experiments. M.M. contributed to Figure 4. T.R. analyzed mass spectrometry data.

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Correspondence to Tobias P Dick.

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Stöcker, S., Maurer, M., Ruppert, T. et al. A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation. Nat Chem Biol 14, 148–155 (2018). https://doi.org/10.1038/nchembio.2536

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