Pharmaceutical Sciences Faculty Publications
Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin.
Document Type
Article
Publication Date
10-1-2009
Journal Title
Nature Cell Biology
ISSN
1476-4679
Volume
11
Issue
10
First Page
1241
Last Page
1246
DOI
10.1038/ncb1968
PubMed ID
19734890
PubMed Central® ID
PMC3393095
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.
Keywords
Alanine, amino acid substitution, apoptosis, COS cells, cysteine, enzyme activation, enzyme inhibitors, etoposide, fibroblasts, Humans, hydrogen peroxide, mitochondria, liver, oxidants, plasmids, RNA
Recommended Citation
Klamt, Fábio; Zdanov, Stéphanie; Levine, Rodney L.; Pariser, Ashley; Zhang, Yaqin; Zhang, Baolin; Yu, Li-Rong; Veenstra, Timothy D.; and Shacter, Emily, "Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin." (2009). Pharmaceutical Sciences Faculty Publications. 303.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/303