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

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.

Stress contingent changes in Hog1 pathway architecture and regulation inCandida albicans

“…This is consistent with work in other organisms showing that protein tyrosine kinases are susceptible to oxidative-stress mediated inhibition through oxidation of the active site cysteine residue (63). Furthermore, a recent study in the fission yeast S. pombe , revealed that oxidation of the Pyp1 protein tyrosine phosphatase to slower migrating disulfide-bonded complexes, contributes to increases in Sty1 phosphorylation (48). Excitingly, we find that the C. albicans Ptp3 phosphatase is oxidised to slower migrating disulfide-bonded complexes following oxidative stress.…”

Redox Regulation of Brain Selective Kinases BRSK1/2: Implications for Dynamic Control of the Eukaryotic AMPK family through Cys-based mechanisms

“…Understanding the molecular mechanisms underlying kinase regulation by redox-active Cys residues is fundamental as it appears to be widespread in signaling proteins (Xiao et al 2020 ;Corcoran and Cotter 2013 ;Cao et al 2023 ) and provides new opportunities to develop specific covalent compounds for the targeted modulation of protein kinases (Weisner et al 2015 ). Moreover, redox-active Cys are major sensors of Reactive Oxygen Species (ROS), such as superoxide and peroxide, which function as endogenous secondary messengers to regulate various cellular processes (Schieber and Chandel 2014 ;Wani et al 2011 ).…”

Redox Regulation of Brain Selective Kinases BRSK1/2: Implications for Dynamic Control of the Eukaryotic AMPK family through Cys-based mechanisms

“…Understanding the molecular mechanisms underlying kinase regulation by redox-active Cys residues is fundamental as it appears to be widespread in signaling proteins (Xiao et al 2020 ;Corcoran and Cotter 2013 ;Cao et al 2023 ) and provides new opportunities to develop specific covalent compounds for the targeted modulation of protein kinases (Weisner et al 2015 ). Moreover, redox-active Cys are major sensors of Reactive Oxygen Species (ROS), such as superoxide and peroxide, which function as secondary messengers to regulate various cellular processes (Schieber and Chandel 2014 ; (Wani et al 2011 ).…”