Abstract
The adenovirus E1B 19K gene product is an inhibitor of apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) during viral infection. We report that E1B 19K inhibited neither caspase-8 activation nor caspase-8-dependent Bid cleavage by TNF-alpha. Rather, TNF-alpha induced a tBid-dependent conformational change in Bax that allowed an interaction between E1B 19K and conformationally altered Bax, which caused inhibition of cytochrome c release and caspase-9 activation. E1B 19K expression interrupted caspase-3 processing, permitting cleavage to remove the p12 subunit but not the prodomain consistent with caspase-8 and not caspase-9 enzymatic activity. Thus, E1B 19K blocks TNF-alpha-mediated death signaling by inhibiting a specific form of Bax that interrupts caspase activation downstream of caspase-8 and upstream of caspase-9.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenovirus E1B Proteins / genetics
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Adenovirus E1B Proteins / metabolism*
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Apoptosis / physiology*
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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 3
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Cytochrome c Group / metabolism
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Enzyme Activation
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Enzyme Precursors / metabolism
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HeLa Cells
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Humans
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Protein Conformation
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2*
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Signal Transduction
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Transfection
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Tumor Necrosis Factor-alpha / metabolism*
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bcl-2-Associated X Protein
Substances
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Adenovirus E1B Proteins
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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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Enzyme Precursors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases