Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas.
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.
Anathy
Vikas
V
Department of Pathology, University of Vermont, Burlington, VT 05405, USA.
Aesif
Scott W
SW
Guala
Amy S
AS
Havermans
Marije
M
Reynaert
Niki L
NL
Ho
Ye-Shih
YS
Budd
Ralph C
RC
Janssen-Heininger
Yvonne M W
YM
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D004847:Epithelial Cells / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D054477:Glutaredoxins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D020169:Caspases; D005978:Glutathione