H2O2 levels linked to cell fitness, signaling and toxicity
Oxidative stress has traditionally been linked to damage, but intracellular fluctuations of hydrogen peroxide (H2O2) can also activate antioxidant pathways.Establishing the intracellular concentrations linked to signaling or to toxicity is not a trivial issue, and we have developed genetically encoded reporters to monitor cytosolic H2O2 fluctuations arising from exogenous sources or from mitochondrial activity.
Anti-oxidant signaling cascades, namely the Pap1 and Sty1 pathways, are essential for stress survival.We aim at understanding the molecular basis of the massive shift of the gene expression program driven by the transcription factors Pap1 and Atf1.Another goal of our group is to understand why some cysteine residues in protein sensors are reversibly oxidized by peroxides, and which electron donor systems (thioredoxins and/or glutaredoxins) restore the inactive state of these sensors.
Finally, numerous experimental evidences indicate that stress responses and respiratory metabolism are linked, and we are investigating the cross-talk between glucose-responding and stress-dependent cascades, and its connection to a healthy aging.
Zuin et al. (2010) Life-span extension by calorie restriction relies on the Sty1 MAP kinase stress pathway. EMBO J. 29:981-991.
Calvo et al. (2013) Dissection of a redox relay: H2O2-dependent activation of the transcription factor Pap1 through the peroxidatic Tpx1-thioredoxin cycle.Cell Rep. 5:1413-1424.
García-Santamarina et al. (2014) Monitoring in vivo reversible cysteine oxidation in proteins using ICAT and mass spectrometry.Nature Prot. 9:1131-1145.
Boronat et al. (2017) Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase.PLoS Genet. 13:e1006858.
Domènech et al. (2018) Using in vivo oxidation status of one- and two-component redox relays to determine H2O2 levels linked to signaling and toxicity.BMC Biol. 16:61.
Salat-Canela et al. (2017) Deciphering the role of the signal- and Sty1 kinase-dependent phosphorylation of the stress-responsive transcription factor Atf1 on gene activation. J. Biol. Chem. 292:13635-13644.
Carmona et al. (2019) Monitoring cytosolic H2O2 fluctuations arising from altered plasma membrane gradients or from mitochondrial activity. Nat. Commun. 10:4526.