title: Modulation of cell death by Bcl-XL through caspase interaction.
abstract: The caspases are cysteine proteases that have been implicated in the execution of programmed cell death in organisms ranging from nematodes to humans. Many members of the Bcl-2 family, including Bcl-XL, are potent inhibitors of programmed cell death and inhibit activation of caspases in cells. Here, we report a direct interaction between caspases and Bcl-XL. The loop domain of Bcl-XL is cleaved by caspases in vitro and in cells induced to undergo apoptotic death after Sindbis virus infection or interleukin 3 withdrawal. Mutation of the caspase cleavage site in Bcl-XL in conjunction with a mutation in the BH1 homology domain impairs the death-inhibitory activity of Bcl-XL, suggesting that interaction of Bcl-XL with caspases may be an important mechanism of inhibiting cell death. However, once Bcl-XL is cleaved, the C-terminal fragment of Bcl-XL potently induces apoptosis. Taken together, these findings indicate that the recognition/cleavage site of Bcl-XL may facilitate protection against cell death by acting at the level of caspase activation and that cleavage of Bcl-XL during the execution phase of cell death converts Bcl-XL from a protective to a lethal protein.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins University Schools of Public Health and Medicine, Baltimore, MD 21205, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Clem
authors.forename: E H
authors.initials: EH
authors.lastname: Cheng
authors.forename: C L
authors.initials: CL
authors.lastname: Karp
authors.forename: D G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: K
authors.initials: K
authors.lastname: Ueno
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
authors.forename: D E
authors.initials: DE
authors.lastname: Griffin
authors.forename: W C
authors.initials: WC
authors.lastname: Earnshaw
authors.forename: M A
authors.initials: MA
authors.lastname: Veliuona
authors.forename: J M
authors.initials: JM
authors.lastname: Hardwick
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004789:Enzyme Activation; D004926:Escherichia coli; D006801:Humans; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003546:Cysteine Endopeptidases