title: Loss of caspase-9 provides genetic evidence for the type I/II concept of CD95-mediated apoptosis.
abstract: The death receptor CD95 triggers apoptosis upon formation of a death-inducing signaling complex and the activation of caspase-8. Two types of CD95-mediated apoptosis have been distinguished that differ in their efficiency of death-inducing signaling complex formation and the requirement of mitochondria for caspase activation. The validity of the type I/II model, however, has been challenged, as Bcl-2 expression or the use of various CD95 agonists resulted in different apoptosis effects. By identifying a caspase-9-deficient T cell line, we now provide genetic evidence for the two-pathway model of CD95-mediated apoptosis and demonstrate that type II cells strongly depend on caspase-9. Caspase-9-deficient cells revealed strongly impaired apoptosis, caspase activation, and mitochondrial membrane depolarization upon CD95 triggering, whereas, surprisingly, activation of Bak and cytochrome c release were not inhibited. Furthermore, caspase-9-deficient cells did not switch to necrosis, and reconstitution of caspase-9 expression restored CD95 sensitivity. Finally, we also show that different death receptors have a distinct requirement for caspase-9.
authors.affiliation: Institute of Molecular Medicine, University of Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Ajoy K
authors.initials: AK
authors.lastname: Samraj
authors.forename: Eric
authors.initials: E
authors.lastname: Keil
authors.forename: Nana
authors.initials: N
authors.lastname: Ueffing
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D053453:Caspase 9 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D051336:Mitochondrial Membranes / Q000201:enzymology; D010539:Permeability; D019014:fas Receptor / Q000502:physiology*
chemical_list: D019014:fas Receptor; D053453:Caspase 9