Sutton Vivien R, Wowk Michelle E, Cancilla Michael, Trapani Joseph A
Cancer Immunology Program, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, 8006, Melbourne, Australia.
Immunity. 2003 Mar;18(3):319-29. doi: 10.1016/s1074-7613(03)00050-5.
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.
颗粒酶B诱导的凋亡涉及半胱天冬酶依赖性靶细胞死亡途径的激活。在此，我们发现颗粒酶B启动半胱天冬酶的加工，但在完整的Jurkat T白血病细胞或NT2神经元细胞中不能完全加工原半胱天冬酶-3。相反，促凋亡介质细胞色素c、Smac/Diablo和HtrA2/Omi从线粒体释放，促进了由自身加工导致的半胱天冬酶的完全激活。线粒体中Bcl-2的过表达抑制了这些促凋亡分子的释放，尽管颗粒酶B对原半胱天冬酶进行了部分加工，但细胞仍存活。我们提出，凋亡抑制蛋白（IAP）与部分加工的原半胱天冬酶结合会抑制细胞死亡，除非线粒体也因颗粒酶B或活化的BH3结构域蛋白（如截短的Bid）而发生破坏。
