Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Cell Division
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Cell Line, Tumor
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Cell Survival
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Cells, Cultured
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Heat-Shock Proteins / chemistry
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Hydrogen Peroxide / metabolism
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Molecular Sequence Data
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Mutation
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxidation-Reduction
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Oxidoreductases / genetics
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Oxidoreductases / metabolism
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Peroxidases / chemistry*
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Peroxidases / metabolism*
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Peroxiredoxins
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RNA, Small Interfering
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Reactive Oxygen Species / metabolism
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Recombinant Proteins / metabolism
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Tumor Suppressor Protein p53 / metabolism
Substances
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Heat-Shock Proteins
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Nuclear Proteins
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RNA, Small Interfering
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Reactive Oxygen Species
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Recombinant Proteins
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SESN1 protein, human
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SESN2 protein, human
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Tumor Suppressor Protein p53
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Hydrogen Peroxide
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Oxidoreductases
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Peroxidases
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Peroxiredoxins