Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions.

Details

Serval ID
serval:BIB_EEC02EF7F1C8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions.
Journal
Journal of Biological Chemistry
Author(s)
Viard-Leveugle I., Bullani R.R., Meda P., Micheau O., Limat A., Saurat J.H., Tschopp J., French L.E.
ISSN
0021-9258
Publication state
Published
Issued date
05/2003
Peer-reviewed
Oui
Volume
278
Number
18
Pages
16183-16188
Language
english
Notes
Publication types: Journal Article
Abstract
Acquired Fas ligand (FasL)-mediated cytolytic activity of human keratinocytes causes the massive keratinocyte cell death that occurs during toxic epidermal necrolysis, a deadly adverse drug eruption. Under normal conditions keratinocyte apoptosis is a rare event in the epidermis although keratinocytes express the death receptor Fas and its ligand. Here we have investigated why this is so. We show that Fas, FasL, Fas-associated death domain, and caspase-8 mRNA are detectable in the epidermis, primary keratinocyte cultures, and keratinocyte cell line and that Fas protein is expressed in keratinocytes of all subcorneal layers of the epidermis, whereas FasL is only expressed in the basal and first suprabasal layers. Coexpression of Fas and FasL therefore occurs in basal and suprabasal keratinocytes. In vitro, keratinocytes are killed by recombinant FasL in a dose-dependent manner, but they are unable to kill Fas-sensitive target cells despite FasL expression. Analysis of keratinocyte culture supernatants and treatment of keratinocytes with metalloproteinase inhibitors excluded cell surface expression of FasL and rapid metalloproteinase-mediated cleavage of cell surface FasL. Fluorescence-activated cell sorter, confocal microscopical, and electron microscopical analysis revealed that keratinocyte FasL is localized intracellularly predominantly associated to intermediate filaments. These data suggest that the observed inability of keratinocyte FasL to induce apoptosis under physiological conditions is due to its cellular localization and also indicate that intermediate filaments may be involved in regulating the subcellular localization of FasL.
Keywords
Adaptor Proteins, Signal Transducing, Apoptosis, Carrier Proteins/physiology, Cells, Cultured, Cytoplasm/chemistry, Fas Ligand Protein, Fas-Associated Death Domain Protein, Humans, Keratinocytes/chemistry, Keratinocytes/cytology, Membrane Glycoproteins/analysis, Membrane Glycoproteins/physiology, Microscopy, Immunoelectron
Pubmed
Web of science
Create date
24/01/2008 15:19
Last modification date
20/08/2019 16:16
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