title: Toxoplasma gondii inhibits Fas/CD95-triggered cell death by inducing aberrant processing and degradation of caspase 8.
abstract: Ligation of the death receptor Fas/CD95 activates an apoptotic cascade and plays critical roles during infectious diseases. Previous work has established that infection with the intracellular parasite Toxoplasma gondii renders cells resistant to multiple inducers of apoptosis. However, the effect of T. gondii on the death receptor pathway is poorly characterized. Here we have determined the impact of the parasite on apoptosis in type I cells that transduce Fas/CD95 engagement via the death receptor pathway without the need of a mitochondrial amplification loop. The results have shown that T. gondii significantly reduced Fas/CD95-triggered apoptosis by impairing activation of the initiator caspase 8. Parasitic infection diminished the cellular amount of procaspase 8, resulting in its decreased recruitment to the death-inducing signalling complex and the impaired activation of effector caspases. Remarkably, downregulation of caspase 8 protein in T. gondii-infected cells also occurred in the absence of Fas/CD95 engagement and was associated with the appearance of non-canonical caspase 8 cleavage fragments. Distinct parasite proteins were associated with caspase 8 and its proteolytic fragments. These findings indicate that T. gondii aberrantly processes and finally degrades the initiator caspase 8, thereby, blocking Fas/CD95-mediated apoptosis which signals independently of the apoptogenic function of host cell mitochondria.
authors.affiliation: Institute for Medical Microbiology, Georg-August-University, Göttingen, Germany.
authors.forename: Polya
authors.initials: P
authors.lastname: Vutova
authors.forename: Martina
authors.initials: M
authors.lastname: Wirth
authors.forename: Diana
authors.initials: D
authors.lastname: Hippe
authors.forename: Uwe
authors.initials: U
authors.lastname: Gross
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
authors.forename: Carsten G K
authors.initials: CG
authors.lastname: Lüder
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000469:parasitology*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D006801:Humans; D014122:Toxoplasma / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D019014:fas Receptor; D053181:Caspase 8