title: The C-terminal domain of the long form of cellular FLICE-inhibitory protein (c-FLIPL) inhibits the interaction of the caspase 8 prodomain with the receptor-interacting protein 1 (RIP1) death domain and regulates caspase 8-dependent nuclear factor κB (NF-κB) activation.
abstract: Caspase 8 plays an essential role in the regulation of apoptotic and non-apoptotic signaling pathways. The long form of cellular FLICE-inhibitory protein (c-FLIPL) has been shown previously to regulate caspase 8-dependent nuclear factor κB (NF-κB) activation by receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). In this study, the molecular mechanism by which c-FLIPL regulates caspase 8-dependent NF-κB activation was further explored in the human embryonic kidney cell line HEK 293 and variant cells barely expressing caspase 8. The caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone greatly diminished caspase 8-dependent NF-κB activation induced by Fas ligand (FasL) when c-FLIPL, but not its N-terminal fragment c-FLIP(p43), was expressed. The prodomain of caspase 8 was found to interact with the RIP1 death domain and to be sufficient to mediate NF-κB activation induced by FasL or c-FLIP(p43). The interaction of the RIP1 death domain with caspase 8 was inhibited by c-FLIPL but not c-FLIP(p43). Thus, these results reveal that the C-terminal domain of c-FLIPL specifically inhibits the interaction of the caspase 8 prodomain with the RIP1 death domain and, thereby, regulates caspase 8-dependent NF-κB activation.
authors.affiliation: From the Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan and.
authors.forename: Iyo
authors.initials: I
authors.lastname: Matsuda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Haruna
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Niwa
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: C119724:AGFG1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D011480:Protease Inhibitors; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Caspase; Death Domain; Fas; NF-κB; RIP