Abstract
Tumor necrosis factor (TNFalpha) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-kappaB and the kinase, JNK. While activation of caspase 8 is required for TNFalpha-induced apoptosis, and induction of NF-kappaB inhibits cell death, the precise function of JNK activation in TNFalpha signaling is not clearly understood. Here, we report that TNFalpha-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / metabolism
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HeLa Cells
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Humans
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I-kappa B Kinase
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases
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Mice
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Mitochondria / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology*
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Bid protein, mouse
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Carrier Proteins
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DIABLO protein, human
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Diablo protein, mouse
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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RNA, Small Interfering
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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CASP8 protein, human
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CASP9 protein, human
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 8
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Caspase 9
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Caspases