A redox-sensitive thiol in Wis1 modulates the fission yeast MAPK response to H2O2 and is the target of a small molecule

Johanna J. Sjölander , Agata Tarczykowska , Cecilia Picazo , Itziar Cossio , Itedale Namro Redwan , Chunxia Gao , Carlos Solano , Michel B. Toledano (1, 2) , Morten Grøtli , Mikael Molin , Per Sunnerhagen

1 I2BC - Institut de Biologie Intégrative de la Cellule
2 SOC - Stress Oxydatif et Cancer

Oxidation of a highly-conserved cysteine (Cys) residue located in the kinase-activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro. We found that C458 is oxidized in vivo and that serine substitution of this residue significantly enhances Wis1 activation upon addition of H2O2 The allosteric MAPKK inhibitor, INR119, which binds in a pocket next to the activation loop and C458 prevented the inhibition of Wis1 by H2O2in vitro, and significantly increased Wis1 activation by low levels of H2O2in vivo We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.

Domaines: Sciences du Vivant [q-bio]

Johanna J. Sjölander, Agata Tarczykowska, Cecilia Picazo, Itziar Cossio, Itedale Namro Redwan, et al.. A redox-sensitive thiol in Wis1 modulates the fission yeast MAPK response to H2O2 and is the target of a small molecule. Molecular and Cellular Biology, 2020, ⟨10.1128/MCB.00346-19⟩. ⟨hal-02445549⟩