Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 192, Issue 10, Pages 1391-1401Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.192.10.1391
Keywords
cytotoxic T lymphocyte; granzyme B; Bcl-2; Bid; Bax
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Cytotoxic T lymphocytcs (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. Wt 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 rum, 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.
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