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
The Journal of Experimental Medicine – Rockefeller University Press
Published: Nov 20, 2000
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