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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2384-2391.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-07-2883.
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Submitted July 20, 2005
Accepted October 27, 2005
Fas Ligand is localized to membrane rafts where it displays increased cell death-inducing activity
Nathalie Cahuzac, Wiebke Baum, Vladimir Kirkin, Fabien Conchonaud, Laure Wawrezinieck, Didier Marguet, Ottmar Janssen, Martin Zornig, and Anne-Odile Hueber*
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A. Lacassagne, Nice, France
Georg-Speyer-Haus, Chemotherapeutisches Forschungsinstitut, Frankfurt, Germany
Centre d'Immunologie de Marseille Luminy, CNRS UMR 6102, INSERM UMR 631, Univ. de la Mediterranee, Marseille, France
Institute of Immunology, Institute of Immunology University Hospital Schleswig-Holstein Campus, Kiel, Germany
* Corresponding author; email: hueber{at}unice.fr.
Fas ligand (FasL), a member of the TNF protein family, potently induces cell death by activating its matching receptor Fas. Fas-mediated killing plays a critical role in both naturally and pathologically occurring cell death, including development and homeostasis of the immune system. In addition to its receptor-interacting and cell death-inducing extracellular domain, FasL possesses a well-conserved intracellular portion with a proline-rich SH3 domain binding site, probably involved in non-apoptotic functions. We report here that, similarly to the Fas receptor, a fraction of FasL is constitutively localized in rafts. These dynamic membrane microdomains enriched in sphingolipids and cholesterol are important for cell signaling and trafficking processes. We show that FasL is partially localized in rafts, and that increased amounts of FasL are found in rafts after efficient FasL-Fas receptor interactions. Both raft disorganization following cholesterol oxidase treatment and deletions within the intracellular FasL domain diminish raft partitioning, and most importantly lead to decreased FasL killing.
We conclude that FasL is recruited into lipid rafts for maximum Fas receptor contact and cell death-inducing potency. These findings raise the possibility that certain pathologic conditions may be treated by altering the cell death-inducing capability of FasL with drugs affecting its raft localization.
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