An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes.
Fas, a member of the tumor necrosis factor receptor family, can upon ligation by its ligand or agonistic antibodies trigger signaling cascades leading to cell death in lymphocytes and other cell types. Such signaling cascades are initiated through the formation of a membrane death-inducing signaling complex (DISC) that includes Fas, the Fas-associated death domain protein (FADD) and caspase-8. We report here that a considerable fraction of Fas is constitutively partitioned into sphingolipid- and cholesterol-rich membrane rafts in mouse thymocytes as well as the L12.10-Fas T cells, and Fas ligation promotes a rapid and specific recruitment of FADD and caspase-8 to the rafts. Raft disruption by cholesterol depletion abolishes Fas-triggered recruitment of FADD and caspase-8 to the membrane, DISC formation and cell death. Taken together, our results provide the first demonstration for an essential role of membrane rafts in the initiation of Fas-mediated cell death signaling.
Hueber
Anne-Odile
AO
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue de Valombrose, 06189 Nice cedex, France. hueber@unice.fr
Bernard
Anne-Marie
AM
Herincs
Zoltan
Z
Couzinet
Arnaud
A
He
Hai-Tao
HT
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D019014:fas Receptor