Abstract
Smac/DIABLO is a mitochondrial protein that is released along with cytochrome c during apoptosis and promotes cytochrome c-dependent caspase activation by neutralizing inhibitor of apoptosis proteins (IAPs). We provide evidence that Smac/DIABLO functions at the levels of both the Apaf-1-caspase-9 apoptosome and effector caspases. The N terminus of Smac/DIABLO is absolutely required for its ability to interact with the baculovirus IAP repeat (BIR3) of XIAP and to promote cytochrome c-dependent caspase activation. However, it is less critical for its ability to interact with BIR1/BIR2 of XIAP and to promote the activity of the effector caspases. Consistent with the ability of Smac/DIABLO to function at the level of the effector caspases, expression of a cytosolic Smac/DIABLO in Type II cells allowed TRAIL to bypass Bcl-xL inhibition of death receptor-induced apoptosis. Combined, these data suggest that Smac/DIABLO plays a critical role in neutralizing IAP inhibition of the effector caspases in the death receptor pathway of Type II cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Apoptosis Regulatory Proteins
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Apoptosis* / drug effects
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / pharmacology
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Carrier Proteins / chemistry*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase Inhibitors
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Caspases / metabolism*
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Cell Differentiation
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Cytosol / chemistry
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Enzyme Activation
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Humans
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Inhibitor of Apoptosis Proteins
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Insect Proteins*
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / metabolism
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Mitochondria / metabolism
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Mitochondrial Proteins*
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Molecular Sequence Data
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Mutation / genetics
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Protein Binding
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proteins / chemistry
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction* / drug effects
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TNF-Related Apoptosis-Inducing Ligand
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
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X-Linked Inhibitor of Apoptosis Protein
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bcl-X Protein
Substances
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Apoptosis Regulatory Proteins
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BCL2L1 protein, human
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Bacterial Proteins
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Carrier Proteins
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Caspase Inhibitors
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DIABLO protein, human
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Inhibitor of Apoptosis Proteins
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Insect Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Mitochondrial Proteins
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Protein Isoforms
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-X Protein
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Caspases