Oxidative processing of latent Fas in the endoplasmic reticulum controls the strength of apoptosis.

Abstract

We recently demonstrated that S-glutathionylation of the death receptor Fas (Fas-SSG) amplifies apoptosis (V. Anathy et al., J. Cell Biol. 184:241-252, 2009). In the present study, we demonstrate that distinct pools of Fas exist in cells. Upon ligation of surface Fas, a separate pool of latent Fas in the endoplasmic reticulum (ER) underwent rapid oxidative processing characterized by the loss of free sulfhydryl content (Fas-SH) and resultant increases in S-glutathionylation of Cys294, leading to increases of surface Fas. Stimulation with FasL rapidly induced associations of Fas with ERp57 and glutathione S-transferase π (GSTP), a protein disulfide isomerase and catalyst of S-glutathionylation, respectively, in the ER. Knockdown or inhibition of ERp57 and GSTP1 substantially decreased FasL-induced oxidative processing and S-glutathionylation of Fas, resulting in decreased death-inducing signaling complex formation and caspase activity and enhanced survival. Bleomycin-induced pulmonary fibrosis was accompanied by increased interactions between Fas-ERp57-GSTP1 and S-glutathionylation of Fas. Importantly, fibrosis was largely prevented following short interfering RNA-mediated ablation of ERp57 and GSTP. Collectively, these findings illuminate a regulatory switch, a ligand-initiated oxidative processing of latent Fas, that controls the strength of apoptosis.

• Authors: Vikas Anathy, Elle Roberson, Brian Cunniff, James D Nolin, Sidra Hoffman, Page Spiess, Amy S Guala, Karolyn G Lahue, Dylan Goldman, Stevenson Flemer, Albert van der Vliet, Nicholas H Heintz, Ralph C Budd, Kenneth D Tew, Yvonne M W Janssen-Heininger
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 32 Issue 17 Pg. 3464-78 (Sep 2012) ISSN: 1098-5549 [Electronic] United States
• PMID: 22751926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cdkn1c protein, mouse
• Cyclin-Dependent Kinase Inhibitor p57
• Fas Ligand Protein
• fas Receptor
• Bleomycin
• Glutathione S-Transferase pi
• Caspases
• Glutathione

Topics

• Amino Acid Sequence
• Animals
• Apoptosis
• Bleomycin
• Caspases (metabolism)
• Cell Line
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p57 (antagonists & inhibitors, genetics, metabolism)
• Endoplasmic Reticulum (metabolism)
• Fas Ligand Protein (metabolism)
• Gene Knockdown Techniques
• Glutathione (metabolism)
• Glutathione S-Transferase pi (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Oxidation-Reduction
• Pulmonary Fibrosis (chemically induced, genetics, pathology)
• Up-Regulation
• fas Receptor (chemistry, metabolism)