Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1
Copyright policy )Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1
By transfection of Coxsackievirus B3 (CVB3) individual protease gene into HeLa cells, we demonstrated that 2A(pro) and 3C(pro) induced apoptosis through multiple converging pathways. Firstly, both 2A(pro) and 3C(pro) induced caspase-8-mediated activation of caspase-3 and dramatically reduced cell viability. Secondly, they both activated the intrinsic mitochondria-mediated apoptosis pathway leading to cytochrome c release from mitochondria and activation of caspase-9. However, 3C(pro) induced these events via both up-regulation of Bax and cleavage of Bid, and 2A(pro) induced these events via cleavage of Bid only. Nevertheless, neither altered Bcl-2 expression. Thirdly, both proteases induced cell death through cleavage or down regulation of cellular factors for translation and transcription: both 2A(pro) and 3C(pro) cleaved eukaryotic translation initiation factor 4GI but their cleavage products are different, indicating different cleavage sites; further, both 2A(pro) and 3C(pro) down-regulated cyclic AMP responsive element binding protein, a transcription factor, with 2A(pro) exhibiting a stronger effect than 3C(pro). Surprisingly, neither could cleave DAP5/p97/NAT1, a translation regulator, although this cleavage was observed during CVB3 infection and could not be blocked by caspase inhibitor z-VAD-fmk. Taken together, these data suggest that 2A(pro) and 3C(pro) induce apoptosis through both activation of proapoptotic mediators and suppression of translation and transcription.
- St. Paul's Hospital Canada
- University of British Columbia Canada
Adult, 3C Viral Proteases, Cytochromes c, Apoptosis, Caspase Inhibitors, Caspase 9, Mitochondria, Enzyme Activation, Cysteine Endopeptidases, Viral Proteins, Proto-Oncogene Proteins c-bcl-2, Humans, Child, Eukaryotic Initiation Factor-4G, Cell Shape, BH3 Interacting Domain Death Agonist Protein, HeLa Cells, bcl-2-Associated X Protein
Adult, 3C Viral Proteases, Cytochromes c, Apoptosis, Caspase Inhibitors, Caspase 9, Mitochondria, Enzyme Activation, Cysteine Endopeptidases, Viral Proteins, Proto-Oncogene Proteins c-bcl-2, Humans, Child, Eukaryotic Initiation Factor-4G, Cell Shape, BH3 Interacting Domain Death Agonist Protein, HeLa Cells, bcl-2-Associated X Protein
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