title: Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin.
abstract: Physiological oxidants that are generated by activated phagocytes comprise the main source of oxidative stress during inflammation. Oxidants such as taurine chloramine (TnCl) and hydrogen peroxide (H(2)O(2)) can damage proteins and induce apoptosis, but the role of specific protein oxidation in this process has not been defined. We found that the actin-binding protein cofilin is a key target of oxidation. When oxidation of this single regulatory protein is prevented, oxidant-induced apoptosis is inhibited. Oxidation of cofilin causes it to lose its affinity for actin and to translocate to the mitochondria, where it induces swelling and cytochrome c release by mediating opening of the permeability transition pore (PTP). This occurs independently of Bax activation and requires both oxidation of cofilin Cys residues and dephosphorylation at Ser 3. Knockdown of endogenous cofilin using targeted siRNA inhibits oxidant-induced apoptosis, which is restored by re-expression of wild-type cofilin but not by cofilin containing Cys to Ala mutations. Exposure of cofilin to TnCl results in intramolecular disulphide bonding and oxidation of Met residues to Met sulphoxide, but only Cys oxidation causes cofilin to induce mitochondrial damage.
authors.affiliation: Laboratory of Biochemistry, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Fábio
authors.initials: F
authors.lastname: Klamt
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Zdanov
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Levine
authors.forename: Ashley
authors.initials: A
authors.lastname: Pariser
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Baolin
authors.initials: B
authors.lastname: Zhang
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yu
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Emily
authors.initials: E
authors.lastname: Shacter
mesh_terms: D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D051338:Cofilin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005047:Etoposide / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051338:Cofilin 1; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D016877:Oxidants; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C076615:cytochrome c''; D013654:Taurine; C043410:N-chlorotaurine; D005047:Etoposide; D006861:Hydrogen Peroxide; D003545:Cysteine; D000409:Alanine