Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD

Science. 2004 Apr 23;304(5670):596-600. doi: 10.1126/science.1095569.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Cell Division
  • Cell Line, Tumor
  • Cell Survival
  • Cells, Cultured
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Hydrogen Peroxide / metabolism
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidation-Reduction
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Peroxidases / chemistry*
  • Peroxidases / metabolism*
  • Peroxiredoxins
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Heat-Shock Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Recombinant Proteins
  • SESN1 protein, human
  • SESN2 protein, human
  • Tumor Suppressor Protein p53
  • Hydrogen Peroxide
  • Oxidoreductases
  • Peroxidases
  • Peroxiredoxins