Abstract
Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / metabolism*
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Cell Death
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Cytochrome c Group / metabolism*
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Cytosol / metabolism
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Cytotoxicity, Immunologic
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Granzymes
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Humans
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Intracellular Membranes / metabolism
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Jurkat Cells / virology
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Mitochondria / metabolism*
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Models, Biological
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Protein Processing, Post-Translational
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Protein Transport
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Serine Endopeptidases / metabolism*
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T-Lymphocytes, Cytotoxic / metabolism
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Tumor Cells, Cultured
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Carrier Proteins
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Cytochrome c Group
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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GZMB protein, human
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Granzymes
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Serine Endopeptidases