Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD
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-SO2H, 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.
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We thank I. Verma for the lentivirus vector system used for expression experiments, M. Chernov for sharing expertise in 2D gel separations, and G. Stark and A. Gudkov for critical reading of the manuscript. The work was supported by funds provided by the Lerner Research Institute to P.M.C.
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Science
Volume 304 | Issue 5670
23 April 2004
23 April 2004
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American Association for the Advancement of Science.
Submission history
Received: 12 January 2004
Accepted: 23 March 2004
Published in print: 23 April 2004
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