title: Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2.
abstract: The role and responses of the dimeric DJ-1 protein to cardiac oxidative stress is incompletely understood. H2O2 induces a 50-kDa DJ-1 interprotein homodimer disulfide, known to form between Cys-53 on each subunit. A trimeric 75-kDa DJ-1 complex that mass spectrometry shows contained 2-Cys peroxiredoxin also formed and precedes the appearance of the disulfide dimer. These observations may represent peroxiredoxin sensing and transducing the oxidant signal to DJ-1. The dimeric disulfide DJ-1 complex was stabilized by auranofin, suggesting that thioredoxin recycles it in cells. Higher concentrations of H2O2 concomitantly induce DJ-1 Cys-106 hyperoxidation (sulfination or sulfonation) in myocytes, perfused heart, or HEK cells. An oxidation-resistant C53A DJ-1 shows potentiated H2O2-induced Cys-106 hyperoxidation. DJ-1 also forms multiple disulfides with unknown target proteins during H2O2 treatment, the formation of which is also potentiated in cells expressing the C53A mutant. This suggests that the intersubunit disulfide induces a conformational change that limits Cys-106 forming heterodisulfide protein complexes or from hyperoxidizing. High concentrations of H2O2 also induce cell death, with DJ-1 Cys-106 sulfonation appearing causal in these events, as expressionof C53A DJ-1 enhanced both Cys-106 sulfonation and cell death. Nonetheless, expression of the DJ-1 C106A mutant, which fully prevents hyperoxidation, also showed exacerbated cell death responses to H2O2 A rational explanation for these findings is that DJ-1 Cys-106 forms disulfides with target proteins to limit oxidant-induced cell death. However, when Cys-106 is hyperoxidized, formation of these potentially protective heterodimeric disulfide complexes is limited, and so cell death is exacerbated.
authors.affiliation: From the King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fernandez-Caggiano
authors.affiliation: From the King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom and.
authors.forename: Ewald
authors.initials: E
authors.lastname: Schröder
authors.affiliation: From the King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom and.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: From the King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Burgoyne
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The James Black Centre, King's College Hospital, London SE5 9NU, United Kingdom.
authors.forename: Javier
authors.initials: J
authors.lastname: Barallobre-Barreiro
authors.affiliation: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The James Black Centre, King's College Hospital, London SE5 9NU, United Kingdom.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.affiliation: From the King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom and philip.eaton@kcl.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004220:Disulfides / Q000737:chemistry*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D047468:Immunoprecipitation; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004220:Disulfides; D008869:Microtubule-Associated Proteins; D016877:Oxidants; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1
keywords: Parkinson disease (autosomal recessive, early onset) 7 (PARK7); heart; oxidative stress; peroxiredoxin; redox regulation