title: 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: Department of Pathology, University of Vermont, Burlington, Vermont, USA.
authors: Vikas
authors: V
authors: Anathy
authors: Elle
authors: E
authors: Roberson
authors: Brian
authors: B
authors: Cunniff
authors: James D
authors: JD
authors: Nolin
authors: Sidra
authors: S
authors: Hoffman
authors: Page
authors: P
authors: Spiess
authors: Amy S
authors: AS
authors: Guala
authors: Karolyn G
authors: KG
authors: Lahue
authors: Dylan
authors: D
authors: Goldman
authors: Stevenson
authors: S
authors: Flemer
authors: Albert
authors: A
authors: van der Vliet
authors: Nicholas H
authors: NH
authors: Heintz
authors: Ralph C
authors: RC
authors: Budd
authors: Kenneth D
authors: KD
authors: Tew
authors: Yvonne M W
authors: YM
authors: Janssen-Heininger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation; D019014:fas Receptor / Q000737:chemistry / Q000378:metabolism*
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D053222:Fas Ligand Protein; D019014:fas Receptor; D001761:Bleomycin; D051549:Glutathione S-Transferase pi; D020169:Caspases; D005978:Glutathione