Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation
| Autor: | Christian Scotto, Paul J. Beresford, Judy Lieberman, Antoine Alam, Kamal Sharma, Rafick-Pierre Sekaly, Eric Rhéaume, Walter E. DeWolf, Dennis Lee, Ehsan Sharif-Askari, Mark E. Nuttall |
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| Rok vydání: | 2001 |
| Předmět: |
Programmed cell death
Apoptosis Caspase 3 DNA Fragmentation Article Granzymes General Biochemistry Genetics and Molecular Biology Substrate Specificity Jurkat Cells Caspase-activated DNase Humans Molecular Biology Caspase Binding Sites Deoxyribonucleases Molecular Structure General Immunology and Microbiology biology General Neuroscience Serine Endopeptidases Nuclear Proteins Proteins Caspase Inhibitors Molecular biology Cell biology Enzyme Activation Granzyme B Granzyme Caspases biology.protein DNA fragmentation Apoptosis Regulatory Proteins hormones hormone substitutes and hormone antagonists |
| Zdroj: | The EMBO Journal. 20:3101-3113 |
| ISSN: | 1460-2075 |
| Popis: | The protease granzyme B (GrB) plays a key role in the cytocidal activity during cytotoxic T lymphocyte (CTL)-mediated programmed cell death. Multiple caspases have been identified as direct substrates for GrB, suggesting that the activation of caspases constitutes an important event during CTL-induced cell death. However, recent studies have provided evidence for caspase-independent pathway(s) during CTL-mediated apoptosis. In this study, we demonstrate caspase-independent and direct cleavage of the 45 kDa unit of DNA fragmentation factor (DFF45) by GrB both in vitro and in vivo. Using a novel and selective caspase-3 inhibitor, we show the ability of GrB to process DFF45 directly and mediate DNA fragmentation in the absence of caspase-3 activity. Furthermore, studies with DFF45 mutants reveal that both caspase-3 and GrB share a common cleavage site, which is necessary and sufficient to induce DNA fragmentation in target cells during apoptosis. Together, our data suggest that CTLs possess alternative mechanism(s) for inducing DNA fragmentation without the requirement for caspases. |
| Databáze: | OpenAIRE |
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