DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis.
Granzyme B (GzmB) is a component of cytotoxic lymphocyte granules that can rapidly initiate apoptosis in target cells. While several procaspases are cleaved and activated by GzmB, the absolute requirement of caspase activation for GzmB-induced apoptosis is controversial. In this report, we demonstrate that GzmB can initiate apoptosis in the absence of caspase-3 activity by directly cleaving DFF45/ICAD to liberate activated DFF40/CAD. DFF45/ICAD cleavage occurs less efficiently in cells that lack caspase-3 activity, suggesting that the caspases normally amplify the GzmB death signal. DFF45/ICAD-deficient mouse embryo fibroblasts are partially resistant to GzmB-induced death, demonstrating the biological importance of DFF45/ICAD for GzmB-mediated apoptosis.
Thomas
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DA
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Du
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C
Xu
M
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Wang
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X
Ley
T J
TJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D053938:DNA Fragmentation / Q000276:immunology*; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D007113:Immunity, Innate; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; C109664:caspase-activated DNase inhibitor; D003851:Deoxyribonucleases; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases