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

Peroxiredoxins (Prdxs) utilize reversibly oxidized cysteine residues to reduce peroxides and promote H 2 O 2 signal transduction, including H 2 O 2 -induced activation of P38 MAPK. Prdxs form H 2 O 2 -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 H 2 O 2 -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 H 2 O 2 -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. [Display omitted] • P38-Prdx complexes increase P38 (Sty1/MAPK14) phosphorylation in yeast and human cells • The S. pombe Prdx Tpx1 promotes thioredoxin-dependent oxidation of a MAPK phosphatase • Sty1-Tpx1 complex activity is increased by phosphatase and MAP3K-independent mechanisms • Sty1-Tpx1 complexes form a scaffold supporting non-canonical activation of the Wis1 MAPKK Phosphorylation activates P38 MAPK in response to many stimuli. Cao et al. reveal two mechanisms by which a peroxiredoxin transmits H 2 O 2 signals to P38: (1) forming a Prdx-P38 complex that provides a scaffold for non-canonical activation of P38 MAPKK and (2) alleviating inhibition by a redox-sensitive P38 phosphatase. [ABSTRACT FROM AUTHOR]