CD95 engagement mediates actin-independent and -dependent apoptotic signals

CD95 is a death receptor whose stimulation by either the physiologic ligand CD95L or the agonistic antibodies leads to theformation of a multi-molecular complex termed DISC (death-inducing signaling complex) and the subsequent induction of acaspase-driven apoptotic signal. According to the magnitude of the DISC formation, two types of cells have been identified.Although type I cells generate an important DISC, the complex is barely found in type II cells. Analyzing the early stagesprecedingtheDISCformation,wefoundthatunlikeCD95L,thecommonlyusedagonisticantibodyAPO1-3internalizedthedeathreceptor. Using inhibitors of actin polymerization, we showed that the remodeling of the actin cytoskeleton did not alter thecapping of the CD95 receptor or its partitioning into the lipid rafts. In addition, whereas the disruption of F-actin prevented theinternalization of CD95, the DISC formation and the apoptotic signal induced by the agonistic antibody APO1-3 in type I cells, itdidnotaffectthesignaltriggeredbythesoluble andmembrane-bound CD95L,regardlessofthetypeofcells.Inconclusion,theadditionofAPO1-3ontypeIcellstriggersanactin-dependentapoptoticsignal,whichisabsentormarginalincells(bothtypesIand II) treated with CD95L.Cell Death and Differentiation advance online publication, 14 August 2009; doi:10.1038/cdd.2009.111