Abstract
Cytotoxic lymphocytes employ Granzyme B as a potent initiator of apoptosis to cleave and activate effector caspases. Unexpectedly, cells transfected with Bcl-2 were resistant to granzyme B-induced killing, suggesting that a mitochondrial pathway was critical. Utilizing cells expressing a dominant-negative caspase 9, the current study demonstrated that caspase activation via the apoptosome was not required. Indeed, cleavage of caspase 3 to p20 still occurred in Bcl-2-transfectants but processing to p17 was blocked. This blockade was recapitulated by the Inhibitor-of-Apoptosis-Protein XIAP and relieved by Smac/DIABLO. Thus granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition. Engagement of both pathways is critical for granzyme-induced killing.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / immunology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Carrier Proteins / metabolism
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Caspase 3
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Caspase 9
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Caspase Inhibitors
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Caspases / metabolism*
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Enzyme Activation
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Enzyme Precursors / metabolism
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Genes, bcl-2
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Granzymes
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Humans
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Intracellular Signaling Peptides and Proteins
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Jurkat Cells
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Mitochondrial Proteins / metabolism
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Models, Biological
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Protein Processing, Post-Translational
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Proteins / metabolism
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Serine Endopeptidases / metabolism*
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Transfection
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Caspase Inhibitors
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DIABLO protein, human
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Enzyme Precursors
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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GZMB protein, human
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Granzymes
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Serine Endopeptidases
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CASP3 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 9
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Caspases