Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_1966F35B4E9F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.
Périodique
Journal of Experimental Medicine
Auteur(s)
Schneider P., Holler N., Bodmer J.L., Hahne M., Frei K., Fontana A., Tschopp J.
ISSN
0022-1007 (Print)
ISSN-L
0022-1007
Statut éditorial
Publié
Date de publication
1998
Volume
187
Numéro
8
Pages
1205-1213
Langue
anglais
Résumé
Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-alpha) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected, even though the levels of circulating sFasL are high.
Mots-clé
Amino Acid Sequence, Animals, Apoptosis, Down-Regulation, Fas Ligand Protein, Humans, Liver/pathology, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred BALB C, Models, Biological, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Receptors, Tumor Necrosis Factor/metabolism, Solubility, Tumor Necrosis Factor-alpha/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 16:19
Dernière modification de la notice
20/08/2019 13:50
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