TNF-alpha signals apoptosis through a bid-dependent conformational change in Bax that is inhibited by E1B 19K.
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.
Perez
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Howard Hughes Medical Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
White
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D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D017501:Adenovirus E1B Proteins; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases