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

Lookup NU author(s): Dr Min Cao, Dr Alison Day, Dr Martin Galler, Heather Latimer, Tom Foy, Emilia Dwyer, Elise McDonald, Dr Jeremy Palmer, Professor Brian Morgan, Dr Elizabeth Veal

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Abstract

© 2023 Peroxiredoxins (Prdxs) utilize reversibly oxidized cysteine residues to reduce peroxides and promote H2O2 signal transduction, including H2O2-induced activation of P38 MAPK. Prdxs 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 a Prdx and 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. We demonstrate that a P38-Prdx fusion protein compensates for loss of the yeast scaffold protein Mcs4 and MAP3K activity, driving yeast into mitosis. Based on our findings, we propose that the H2O2-induced formation of Prdx-MAPK disulfide complexes provides an alternative scaffold and signaling platform for MAPKK-MAPK signaling. The demonstration that formation of a complex with a Prdx is sufficient to modify the activity of a kinase has broad implications for peroxide-based signal transduction in eukaryotes.

Publication metadata

Author(s): Cao M, Day AM, Galler M, Latimer HR, Byrne DP, Foy TW, Dwyer E, Bennett E, Palmer J, Morgan BA, Eyers PA, Veal EA

Publication type: Article

Publication status: Published

Journal: Molecular Cell

Year: 2023

Volume: 83

Issue: 17

Pages: 3140-3154.e7

Online publication date: 11/08/2023

Acceptance date: 04/07/2023

ISSN (print): 1097-2765

ISSN (electronic): 1097-4164

Publisher: Cell Press

URL: https://doi.org/10.1016/j.molcel.2023.07.018

DOI: 10.1016/j.molcel.2023.07.018

PubMed id: 37572670

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