Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax

Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction. cytotoxic T lymphocyte granzyme B Bcl-2 Bid Bax Footnotes Abbreviations used in this paper: Ad, adenovirus; DISC, death-inducing signaling complex; grB, granzyme B; HRP, horseradish peroxidase; t, truncated. Submitted: 11 August 2000 Revision requested 18 September 2000 Accepted: 23 September 2000 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax

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Publisher
Rockefeller University Press
Copyright
© 2000 The Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.192.10.1391
Publisher site
See Article on Publisher Site

Abstract

Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction. cytotoxic T lymphocyte granzyme B Bcl-2 Bid Bax Footnotes Abbreviations used in this paper: Ad, adenovirus; DISC, death-inducing signaling complex; grB, granzyme B; HRP, horseradish peroxidase; t, truncated. Submitted: 11 August 2000 Revision requested 18 September 2000 Accepted: 23 September 2000

Journal

The Journal of Experimental MedicineRockefeller University Press

Published: Nov 20, 2000

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