Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin

Fábio Klamt, Stéphanie Zdanov, Rodney L. Levine, Ashley Pariser, Yaqin Zhang, Baolin Zhang, Li-Rong Yu, Timothy D. Veenstra and Emily Shacter

Nat Cell Biol. 2009 Oct;11(10):1241-6.

Student: Yun-Ju Sung (宋昀儒)                             Time: 15:00~16:00 Mar. 3, 2010

Commentator: Chiou-Feng Lin (林秋烽 老師)   Place: Room 601

Abstract:

Reactive oxygen species (ROS) are generated during normal cellular activity and may exist in excess in some pathophysiological conditions, such as inflammation. It is clear that excess levels of free radicals can cause cell death. The pathway of death depends on the type, concentration, source, and environment of the oxidant(s). Taurine chloramine (TnCl), the main oxidant generated by activated neutrophils, has been known to damage proteins and induce apoptosis. Previous studies showed TnCl-induced apoptosis is dependent upon oxidant-mediated mitochondrial damage, and caspase-9 activation¹. Although oxidants regulate cell death, the mechanisms whereby oxidants activate the apoptotic machinery are not well understood, and molecular targets for oxidative modification are not known. Here, the authors report identification of the actin-binding protein cofilin is a key target of oxidation by a proteomic approach after induction of apoptosis by TnCl. Oxidation of cofilin cys residues results in loss of actin-binding activity but translocation to mitochondria, both necessary for the opening of the mitochondrial permeability transition pore and subsequent release of cytochrome c. When oxidation of cofilin is prevented by using small-interfering RNA (siRNA) or replace with cofilin lacking oxidizable cys residues, oxidant-induced apoptosis is inhibited which is restored by re-expression of wild-type cofilin. However, dephosphorylation of cofilin at ser 3 is also required for oxidant-induced Bax-independent apoptosis. Under TnCl treatment, intra-molecular disulfide bonds and oxidation of Met residues also occur in cofilin, but only Cys oxidation residues causes cofilin to induce mitochondrial damage.

References:

1.          Klamt, F. & Shacter, E. Taurine chloramine, an oxidant derived from neutrophils, induces apoptosis in human B lymphoma cells through mitochondrial damage. J. Biol. Chem. 280, 21346–21352 (2005).