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J. Cell Biol. 184 (2): 241-252

Copyright © 2009 by the Rockefeller University Press.

Article

Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas

Vikas Anathy1, Scott W. Aesif1, Amy S. Guala1, Marije Havermans1, Niki L. Reynaert4, Ye-Shih Ho3, Ralph C. Budd2, , and Yvonne M.W. Janssen-Heininger1

1 Department of Pathology and 2 Department of Medicine, University of Vermont, Burlington, VT 05405
3 Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202
4 Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, Netherlands 6229ER

Correspondence to Yvonne M.W. Janssen-Heininger: yvonne.janssen{at}uvm.edu

Abstract: Reactive oxygen species (ROS) increase ligation of Fas (CD95), a receptor important for regulation of programmed cell death. Glutathionylation of reactive cysteines represents an oxidative modification that can be reversed by glutaredoxins (Grxs). The goal of this study was to determine whether Fas is redox regulated under physiological conditions. In this study, we demonstrate that stimulation with Fas ligand (FasL) induces S-glutathionylation of Fas at cysteine 294 independently of nicotinamide adenine dinucleotide phosphate reduced oxidase–induced ROS. Instead, Fas is S-glutathionylated after caspase-dependent degradation of Grx1, increasing subsequent caspase activation and apoptosis. Conversely, overexpression of Grx1 attenuates S-glutathionylation of Fas and partially protects against FasL-induced apoptosis. Redox-mediated Fas modification promotes its aggregation and recruitment into lipid rafts and enhances binding of FasL. As a result, death-inducing signaling complex formation is also increased, and subsequent activation of caspase-8 and -3 is augmented. These results define a novel redox-based mechanism to propagate Fas-dependent apoptosis.

Abbreviations used in this paper: ANOVA, analysis of variance; DD, death domain; DISC, death-inducing signaling complex; DPI, diphenyliodonium; FADD, Fas-associated DD; FasL, Fas ligand; Grx, glutaredoxin; IP, immunoprecipitation; MW, molecular weight; Prx, peroxiredoxin; ROS, reactive oxygen species; WT, wild type.

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