Caspase Activation by Granzyme B Is Indirect, and Caspase Autoprocessing Requires the Release of Proapoptotic Mitochondrial Factors

Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proa...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2003-03, Vol.18 (3), p.319-329
Main Authors: Sutton, Vivien R, Wowk, Michelle E, Cancilla, Michael, Trapani, Joseph A
Format: Article
Language:English
Subjects:
Apoptosis
BH3 Interacting Domain Death Agonist Protein
Carrier Proteins - metabolism
Caspase 3
Caspases - metabolism
Cell Line
Cytochrome c Group - metabolism
Cytotoxicity
Deoxyribonucleic acid
DNA
Enzyme Activation
Gene Expression
Genes, bcl-2
Granzymes
High-Temperature Requirement A Serine Peptidase 2
Humans
Intracellular Signaling Peptides and Proteins
Jurkat Cells
Leukemia
Mitochondria
Mitochondria - metabolism
Mitochondrial Proteins - metabolism
Models, Biological
Molecular weight
Proteins
Proteins - metabolism
Rodents
Scholarships & fellowships
Serine Endopeptidases - metabolism
X-Linked Inhibitor of Apoptosis Protein
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Summary:Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proapoptotic mediators cytochrome c, Smac/Diablo, and HtrA2/Omi facilitates full activation of caspases that results from autoprocessing. Bcl-2 overexpression in mitochondria suppresses the release of these proapoptotic molecules, resulting in cell survival despite partial procaspase processing by granzyme B. We propose that binding of inhibitor of apoptosis (IAP) proteins to partially processed procaspases inhibits cell death unless mitochondrial disruption also occurs in response to granzyme B or activated BH3-domain proteins such as truncated Bid.
ISSN:1074-7613
1097-4180
DOI:10.1016/S1074-7613(03)00050-5