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首页> 外文期刊>EMBO Journal >Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation.
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Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation.

机译：人类DNA的直接裂解碎片factor-45 granzyme B诱发caspase-activatedDNase释放和DNA碎片。

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摘要

The protease granzyme B (GrB) plays a key role in the cytocidal activity during cytotoxic T lymphocyte (CTL)-mediated programmed cell death. Multiple caspases have been identified as direct substrates for GrB, suggesting that the activation of caspases constitutes an important event during CTL-induced cell death. However, recent studies have provided evidence for caspase-independent pathway(s) during CTL-mediated apoptosis. In this study, we demonstrate caspase-independent and direct cleavage of the 45 kDa unit of DNA fragmentation factor (DFF45) by GrB both in vitro and in vivo. Using a novel and selective caspase-3 inhibitor, we show the ability of GrB to process DFF45 directly and mediate DNA fragmentation in the absence of caspase-3 activity. Furthermore, studies with DFF45 mutants reveal that both caspase-3 and GrB share a common cleavage site, which is necessary and sufficient to induce DNA fragmentation in target cells during apoptosis. Together, our data suggest that CTLs possess alternative mechanism(s) for inducing DNA fragmentation without the requirement for caspases.
机译：蛋白酶granzyme B (GrB)起着关键作用在细胞毒性T杀细胞的活动淋巴细胞(CTL)介导的细胞程序性死亡。多个还存在被认定为直接基质对伽马线暴,这表明还构成了一个重要的激活活动期间CTL-induced细胞死亡。最近的研究提供了证据caspase-independent通路(年代)CTL-mediated细胞凋亡。演示caspase-independent和直接劈理的45 kDa单位的DNA碎片因子(DFF45)通过伽马线暴在体外和体内。使用小说和选择性caspase-3抑制剂,我们展示的能力处理DFF45伽马线暴直接和间接的DNA碎片缺乏caspase-3活动。与DFF45突变体的研究表明,两者兼而有之caspase-3和伽马线暴共享一个共同的裂解位点,这是必要的,足以引起DNA碎片在靶细胞凋亡。在一起,我们的数据表明,ctl替代机制(s)诱导的DNA碎片没有要求还存在。

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