Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD.
Acting as a signal, hydrogen peroxide circumvents antioxidant defense by overoxidizing peroxiredoxins (Prxs), the enzymes that metabolize peroxides. We show that sestrins, a family of proteins whose expression is modulated by p53, are required for regeneration of Prxs containing Cys-SO(2)H, thus reestablishing the antioxidant firewall. Sestrins contain a predicted redox-active domain homologous to AhpD, the enzyme catalyzing the reduction of a bacterial Prx, AhpC. Purified Hi95 (sestrin 2) protein supports adenosine triphosphate-dependent reduction of overoxidized PrxI in vitro, indicating that unlike AhpD, which is a disulfide reductase, sestrins are cysteine sulfinyl reductases. As modulators of peroxide signaling and antioxidant defense, sestrins constitute potential therapeutic targets.
Budanov
Andrei V
AV
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Sablina
Anna A
AA
Feinstein
Elena
E
Koonin
Eugene V
EV
Chumakov
Peter M
PM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010544:Peroxidases / Q000737:chemistry* / Q000378:metabolism*; D054464:Peroxiredoxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000084622:Sestrins
D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D009687:Nuclear Proteins; D010088:Oxidoreductases; D010544:Peroxidases; D054464:Peroxiredoxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C117338:SESN1 protein, human; D000084622:Sestrins; C465398:SESN2 protein, human