title: A 2-Cys peroxiredoxin regulates peroxide-induced oxidation and activation of a stress-activated MAP kinase.
abstract: Oxidative stress-induced cell damage is an important component of many diseases and ageing. In eukaryotes, activation of JNK/p38 stress-activated protein kinase (SAPK) signaling pathways is critical for the cellular response to stress. 2-Cys peroxiredoxins (2-Cys Prx) are highly conserved, extremely abundant antioxidant enzymes that catalyze the breakdown of peroxides to protect cells from oxidative stress. Here we reveal that Tpx1, the single 2-Cys Prx in Schizosaccharomyces pombe, is required for the peroxide-induced activation of the p38/JNK homolog, Sty1. Tpx1 activates Sty1, downstream of previously identified redox sensors, by a mechanism that involves formation of a peroxide-induced disulphide complex between Tpx1 and Sty1. We have identified conserved cysteines in Tpx1 and Sty1 that are essential for normal peroxide-induced Tpx1-Sty1 disulphide formation and Tpx1-dependent regulation of peroxide-induced Sty1 activation. Thus we provide new insight into the response of SAPKs to diverse stimuli by revealing a mechanism for SAPK activation specifically by oxidative stress.
authors.affiliation: Institute of Cell and Molecular Biosciences, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom. e.a.veal@ncl.ac.uk
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Veal
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.forename: Alison M
authors.initials: AM
authors.lastname: Day
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Bozonet
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Evans
authors.forename: Janet
authors.initials: J
authors.lastname: Quinn
authors.forename: Brian A
authors.initials: BA
authors.lastname: Morgan
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D003545:Cysteine / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D046911:Macromolecular Substances; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010544:Peroxidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D054464:Peroxiredoxins; D011485:Protein Binding / Q000502:physiology; D012568:Schizosaccharomyces / Q000201:enzymology / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013440:Sulfides / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D016877:Oxidants; D029702:Schizosaccharomyces pombe Proteins; D013440:Sulfides; C515985:Tpx1 protein, S pombe; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D003545:Cysteine