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bioRxiv · 10.1101/2022.11.15.513554

A Peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms

Cao, M.·Day, A. M.·Galler, M.·Latimer, H. R.·Byrne, D.·Bennett, E.·Dwyer, E.·Eyers, P. A.·Veal, E. A.
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Abstract

Peroxiredoxins (Prdx) utilize reversibly oxidized cysteine residues to reduce peroxides but also to promote H2O2 signal transduction, including H2O2-induced activation of P38 MAPK. Prdx form H2O2-induced disulfide complexes with many proteins, including multiple kinases involved in P38 MAPK signaling. Here we show that a genetically-encoded fusion between Prdx and the P38 MAPK is sufficient to hyperactivate the kinase in yeast and human cells by a mechanism that does not require the H2O2-sensing cysteine of the Prdx. In yeast, we demonstrate that a P38-Prdx fusion protein compensates for the loss of a scaffold protein and upstream MAP3K kinase activity, driving entry into mitosis. Based on our findings, we propose that the H2O2-induced formation of Prdx-MAPK disulfide complexes provides a scaffold and signaling platform for MAPKK-MAPK signaling. The demonstration that formation of a complex with a Prdx can be sufficient to modify the activity of a kinase has broad implications for peroxide-based signal transduction in eukaryotes. HighlightsP38-Prdx complexes increase P38 (Sty1/MAPK14) phosphorylation in yeast and human cells The S. pombe Prdx promotes transient thioredoxin-mediated oxidation of a MAPK tyrosine phosphatase P38-Prdx complexes increase P38(Sty1) activity by phosphatase and MAP3K-independent mechanisms P38-Prdx complexes increase the stability and phosphorylation of the S. pombe P38 MAPKK (Wis1) Non-canonical, H2O2-induced autophosphorylation contributes to activation of the Wis1 MAPKK

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Cao, M., Day, A. M., Galler, M., Latimer, H. R., Byrne, D., Bennett, E., Dwyer, E., Eyers, P. A., Veal, E. A.. 2022-11-15. A Peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms. https://doi.org/10.1101/2022.11.15.513554

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