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.
复制标题
颗粒酶B介导的细胞色素C释放受BCL-2家族成员的竞标和BAX的调节。
DOI：
10.1084/jem.192.10.1391
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发表时间：
2000-11-20
影响因子：
15.3
通讯作者：
Bleackley, R C
中科院分区：
文献类型：
--
作者：
Heibein, J A;Goping, I S;Barry, M;Pinkoski, M J;Shore, G C;Green, D R;Bleackley, R C
细胞毒性T淋巴细胞（ctl）破坏靶细胞的机制涉及细胞溶解颗粒成分的胞外分泌，包括颗粒酶B （grB）和穿孔素，它们已被证明通过半胱天冬酶激活诱导细胞凋亡。然而，grB也与半胱天冬酶不依赖的线粒体功能破坏有关。我们在这里表明，细胞色素c的释放需要grB直接对Bid进行蛋白水解裂解，以产生14 kd的grB截断产物（gtBid），该产物易位到线粒体。反过来，gtBid通过caspase不依赖的机制将Bax招募到线粒体，使其整合到膜中并诱导细胞色素c的释放。我们的研究结果为ctl造成损伤的新途径提供了证据，并解释了线粒体功能障碍的caspase独立机制。
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.