RT Journal Article
SR Electronic
T1 A Peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.15.513554
DO 10.1101/2022.11.15.513554
A1 Min Cao
A1 Alison M Day
A1 Martin Galler
A1 Heather Latimer
A1 Dominic P Byrne
A1 Emilia Dwyer
A1 Elise Bennett
A1 Patrick A Eyers
A1 Elizabeth A Veal
YR 2022
UL http://biorxiv.org/content/early/2022/11/15/2022.11.15.513554.abstract
AB 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.Highlights P38-Prdx complexes increase P38 (Sty1/MAPK14) phosphorylation in yeast and human cellsThe S. pombe Prdx promotes transient thioredoxin-mediated oxidation of a MAPK tyrosine phosphataseP38-Prdx complexes increase P38(Sty1) activity by phosphatase and MAP3K-independent mechanismsP38-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 MAPKKCompeting Interest StatementThe authors have declared no competing interest.