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

Copyright © 2009 by the Rockefeller University Press.


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}

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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Genetic ablation of glutaredoxin-1 causes enhanced resolution of airways hyperresponsiveness and mucus metaplasia in mice with allergic airways disease.
S. M. Hoffman, J. E. Tully, K. G. Lahue, V. Anathy, J. D. Nolin, A. S. Guala, J. L. J. van der Velden, Y.-S. Ho, M. Aliyeva, N. Daphtary, et al. (2012)
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   Abstract »    Full Text »    PDF »
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V. Anathy, E. Roberson, B. Cunniff, J. D. Nolin, S. Hoffman, P. Spiess, A. S. Guala, K. G. Lahue, D. Goldman, S. Flemer, et al. (2012)
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   Abstract »    Full Text »    PDF »
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Q. Chang, M. E. Peter, and M. A. Grassi (2012)
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Glutaredoxin 2 prevents aggregation of mutant SOD1 in mitochondria and abolishes its toxicity.
A. Ferri, P. Fiorenzo, M. Nencini, M. Cozzolino, M. G. Pesaresi, C. Valle, S. Sepe, S. Moreno, and M. T. Carri (2010)
Hum. Mol. Genet. 19, 4529-4542
   Abstract »    Full Text »    PDF »
Endogenous HMGB1 regulates autophagy.
D. Tang, R. Kang, K. M. Livesey, C.-W. Cheh, A. Farkas, P. Loughran, G. Hoppe, M. E. Bianchi, K. J. Tracey, H. J. Zeh III, et al. (2010)
J. Cell Biol. 190, 881-892
   Abstract »    Full Text »    PDF »
S-glutathionylation activates STIM1 and alters mitochondrial homeostasis.
B. J. Hawkins, K. M. Irrinki, K. Mallilankaraman, Y.-C. Lien, Y. Wang, C. D. Bhanumathy, R. Subbiah, M. F. Ritchie, J. Soboloff, Y. Baba, et al. (2010)
J. Cell Biol. 190, 391-405
   Abstract »    Full Text »    PDF »
Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I{kappa}B kinases in mice: impact on histone acetylation.
S. Chung, I. K. Sundar, H. Yao, Y.-S. Ho, and I. Rahman (2010)
Am J Physiol Lung Cell Mol Physiol 299, L192-L203
   Abstract »    Full Text »    PDF »
Characterization of caspase-dependent and caspase-independent deaths in glioblastoma cells treated with inhibitors of the ubiquitin-proteasome system.
C. Foti, C. Florean, A. Pezzutto, P. Roncaglia, A. Tomasella, S. Gustincich, and C. Brancolini (2009)
Mol. Cancer Ther. 8, 3140-3150
   Abstract »    Full Text »    PDF »
Apoptotic cells let down their guard.
M. Leslie (2009)
J. Cell Biol. 184, 187
   Full Text »    PDF »

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