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

Mol Cell. 2023 Sep 7;83(17):3140-3154.e7. doi: 10.1016/j.molcel.2023.07.018. Epub 2023 Aug 11.

Abstract

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.

Keywords: MAPK; P38; Schizosaccharomyces pombe; cell-cycle regulation; chaperone; cysteine; fission yeast; kinase; peroxiredoxin; protein tyrosine phosphatase; redox; redox signaling; scaffold; signal transduction; signaling complex; signaling platform; thiol oxidation; thioredoxin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cysteine / metabolism
  • Disulfides
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Oxidation-Reduction
  • Peroxiredoxins* / genetics
  • Peroxiredoxins* / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • p38 Mitogen-Activated Protein Kinases* / genetics
  • p38 Mitogen-Activated Protein Kinases* / metabolism

Substances

  • Cysteine
  • Disulfides
  • Hydrogen Peroxide
  • p38 Mitogen-Activated Protein Kinases
  • Peroxiredoxins