Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis.
Fas is a member of the tumour necrosis factor receptor superfamily. Fas-mediated apoptosis is an essential mechanism protecting against skin cancer. Activation of Fas by specific ligand or agonistic antibodies leads to the formation of a membrane associated death-inducing signalling complex comprising aggregates of Fas, the Fas-associated death domain protein (FADD), and caspase-8. It has recently been suggested that activity of Fas is not only regulated by its cognate ligand but also by the association of this receptor with cholesterol-enriched lipid domains in the plasma membrane (lipid rafts). We report here that disruption of lipid rafts by cholesterol-depleting compounds (methyl-beta-cyclodextrin, filipin III, cholesterol oxidase, and mevastatin) leads to a spontaneous clustering of Fas in the non-raft compartment of the plasma membrane, formation of Fas-FADD complexes, activation of caspase-8, and apoptosis. We propose that in some cell types exclusion of Fas from lipid rafts leads to the spontaneous, ligand-independent activation of this death receptor, a mechanism that can potentially be utilized in anticancer therapy.
Gniadecki
Robert
R
Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark. rg01@bbh.hosp.dk
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002789:Cholesterol Oxidase / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005372:Filipin / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008560:Membrane Fluidity / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*; D047392:beta-Cyclodextrins; D019014:fas Receptor / Q000378:metabolism*
D003505:Cyclodextrins; D008024:Ligands; D047392:beta-Cyclodextrins; D019014:fas Receptor; C108732:methyl-beta-cyclodextrin; C012258:mevastatin; D005372:Filipin; D002784:Cholesterol; D008148:Lovastatin; D002789:Cholesterol Oxidase