| 1. |
- Roger, Friederike, et al.
(författare)
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Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modulation of protein kinase A
- 2020
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Ingår i: eLife. - 2050-084X. ; 9, s. 1-32
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Tidskriftsartikel (refereegranskat)abstract
- Peroxiredoxins are H2O2 scavenging enzymes that also carry out H2O2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H2O2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H2O2, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by H2O2 and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modification of the conserved Cys243 inhibits the phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity, and preventing Thr241 phosphorylation can overcome the H2O2 sensitivity of Tsa1-deficient cells. Results support a model of aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits, including a peroxiredoxin-dependent response to H2O2.
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| 2. |
- Sjölander, Johanna J, 1980, et al.
(författare)
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A redox-sensitive thiol in Wis1 modulates the fission yeast MAPK response to H2O2 and is the target of a small molecule.
- 2020
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 40:7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Sjölander, Johanna J., et al.
(författare)
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A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule
- 2020
-
Ingår i: Molecular and cellular biology. - 1098-5549 .- 0270-7306. ; 40:7
-
Tidskriftsartikel (refereegranskat)abstract
- 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 Schizosaccharomyces pombe 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 replacement 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.
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