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  • Sir Peter MacCallum Department of Oncology
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    Initiation of apoptosis by granzyme B requires direct cleavage of Bid, but not direct granzyme B-mediated caspase activation

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    Author
    Sutton, VR; Davis, JE; Cancilla, M; Johnstone, RW; Ruefli, AA; Sedelies, K; Browne, KA; Trapani, JA
    Date
    2000-11-20
    Source Title
    Journal of Experimental Medicine
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Trapani, Joseph; Johnstone, Ricky
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
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    Document Type
    Journal Article
    Citations
    Sutton, 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.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257747
    DOI
    10.1084/jem.192.10.1403
    Abstract
    The 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.

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