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dc.contributor.authorSutton, VR
dc.contributor.authorDavis, JE
dc.contributor.authorCancilla, M
dc.contributor.authorJohnstone, RW
dc.contributor.authorRuefli, AA
dc.contributor.authorSedelies, K
dc.contributor.authorBrowne, KA
dc.contributor.authorTrapani, JA
dc.date.accessioned2020-12-22T02:57:06Z
dc.date.available2020-12-22T02:57:06Z
dc.date.issued2000-11-20
dc.identifier.citationSutton, V. R., Davis, J. E., Cancilla, M., Johnstone, R. W., Ruefli, A. A., Sedelies, K., Browne, K. A. & Trapani, J. A. (2000). Initiation of apoptosis by granzyme B requires direct cleavage of Bid, but not direct granzyme B-mediated caspase activation. JOURNAL OF EXPERIMENTAL MEDICINE, 192 (10), pp.1403-1413. https://doi.org/10.1084/jem.192.10.1403.
dc.identifier.issn0022-1007
dc.identifier.urihttp://hdl.handle.net/11343/257747
dc.description.abstractThe essential upstream steps in granzyme B-mediated apoptosis remain undefined. Herein, we show that granzyme B triggers the mitochondrial apoptotic pathway through direct cleavage of Bid; however, cleavage of procaspases was stalled when mitochondrial disruption was blocked by Bcl-2. The sensitivity of granzyme B-resistant Bcl-2-overexpressing FDC-P1 cells was restored by coexpression of wild-type Bid, or Bid with a mutation of its caspase-8 cleavage site, and both types of Bid were cleaved. However, Bid with a mutated granzyme B cleavage site remained intact and did not restore apoptosis. Bid with a mutation preventing its interaction with Bcl-2 was cleaved but also failed to restore apoptosis. Rapid Bid cleavage by granzyme B (<2 min) was not delayed by Bcl-2 overexpression. These results clearly placed Bid cleavage upstream of mitochondrial Bcl-2. In granzyme B-treated Jurkat cells, endogenous Bid cleavage and loss of mitochondrial membrane depolarization occurred despite caspase inactivation with z-Val-Ala-Asp-fluoromethylketone or Asp-Glu-Val-Asp-fluoromethylketone. Initial partial processing of procaspase-3 and -8 was observed irrespective of Bcl-2 overexpression; however, later processing was completely abolished by Bcl-2. Overall, our results indicate that mitochondrial perturbation by Bid is necessary to achieve a lethal threshold of caspase activity and cell death due to granzyme B.
dc.languageEnglish
dc.publisherROCKEFELLER UNIV PRESS
dc.titleInitiation of apoptosis by granzyme B requires direct cleavage of Bid, but not direct granzyme B-mediated caspase activation
dc.typeJournal Article
dc.identifier.doi10.1084/jem.192.10.1403
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titleJournal of Experimental Medicine
melbourne.source.volume192
melbourne.source.issue10
melbourne.source.pages1403-1413
dc.rights.licenseCC BY-NC-SA
melbourne.elementsid1126635
melbourne.contributor.authorTrapani, Joseph
melbourne.contributor.authorJohnstone, Ricky
dc.identifier.eissn1540-9538
melbourne.accessrightsOpen Access


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