Caspases induce cytochrome c release from mitochondria by activating cytosolic factors
Caspases induce cytochrome c release from mitochondria by activating cytosolic factors
复制标题
DOI：
10.1074/jbc.274.25.17484
复制
发表时间：
1999-06-18
影响因子：
4.8
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Bossy-Wetzel, E;Green, DR
我们研究了半胱天冬酶（天冬氨酸特异性半胱氨酸蛋白酶）诱导线粒体释放细胞色素c的能力。当通过Fas受体连接诱导Jurkat细胞进行凋亡时，细胞色素c从线粒体释放，这是由半胱天冬酶抑制剂zVAD-favor（zVal-Ala-Asp-CR 2F）阻止的事件。纯化的半胱天冬酶-8触发细胞色素c从离体线粒体中快速释放。这种作用是间接的，因为需要胞质溶胶的存在，表明胱天蛋白酶-8切割并激活胞质溶胶底物，这进而能够诱导细胞色素c从线粒体释放。细胞色素c释放活性不被胱天蛋白酶抑制阻断，但被Bcl-2或Bcl-xL拮抗。半胱天冬酶-8和半胱天冬酶-3裂解Bid，Bid是促凋亡Bcl-2家族成员，其响应于半胱天冬酶裂解而获得细胞色素c释放活性。然而，胱天蛋白酶-6和胱天蛋白酶-7不裂解投标，虽然他们启动细胞色素c从线粒体中的细胞质的存在下释放。因此，效应物半胱天冬酶可以切割并激活另一种胞质底物（除了Bid），其然后促进细胞色素c从线粒体释放。线粒体显著增强了caspase-8启动的DEVD特异性切割活性。我们的数据表明，细胞色素c的释放，启动的行动，半胱天冬酶对胞质底物，可能会采取行动，以放大凋亡过程中的半胱天冬酶级联反应。
We investigated the ability of caspases (cysteine proteases with aspartic acid specificity) to induce cytochrome c release from mitochondria. When Jurkat cells were induced to undergo apoptosis by Fas receptor ligation, cytochrome c was released from mitochondria, an event that was prevented by the caspase inhibitor, zVAD-fmk (zVal-Ala-Asp-CR2F). Purified caspase-8 triggered rapid cytochrome c release from isolated mitochondria in vitro. The effect was indirect, as the presence of cytosol was required, suggesting that caspase-8 cleaves and activates a cytosolic substrate, which in turn is able to induce cytochrome c release from mitochondria, The cytochrome c releasing activity was not blocked by caspase inhibition, but was antagonized by Bcl-2 or Bcl-xL. Caspase-8 and caspase-3 cleaved Bid, a proapoptotic Bcl-2 family member, which gains cytochrome c releasing activity in response to caspase cleavage. However, caspase-6 and caspase-7 did not cleave Bid, although they initiated cytochrome c release from mitochondria in the presence of cytosol. Thus, effector caspases may cleave and activate another cytosolic substrate (other than Bid), which then promotes cytochrome c release from mitochondria. Mitochondria significantly amplified the caspase-8 initiated DEVD-specific cleavage activity. Our data suggest that cytochrome c release, initiated by the action of caspases on a cytosolic substrates, may act to amplify a caspase cascade during apoptosis.