Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c
Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c
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DOI：
10.1074/jbc.273.26.16589
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发表时间：
1998-06-26
影响因子：
4.8
通讯作者：
Kornbluth, S
中科院分区：
文献类型：
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作者：
Kuwana, T;Smith, JJ;Kornbluth, S
细胞凋亡通常涉及线粒体释放细胞色素 c，导致 caspase 激活。然而，在 CD95 (Fas/APO-1) 介导的细胞凋亡中，caspase-8 (FLICE/MACH/Mch5) 立即被激活，原则上可以直接处理其他 caspase。为了研究 caspase-8 是否也可以通过线粒体发挥作用，我们将活性 caspase-8 添加到需要这些细胞器的爪蟾无细胞系统中。 Caspase-8 迅速促进细胞凋亡程序，最终导致染色质和核膜断裂。在不含线粒体的提取物中，caspase-8 产生 DNA 降解，但核膜保持完整。因此，线粒体对于细胞凋亡机制的完全参与是必需的。在没有线粒体的情况下，需要高浓度的 caspase-8 来激活下游 caspase。然而，当线粒体存在时，低浓度 caspase-8 的作用通过细胞色素 c 依赖性 caspase 激活而大大放大。 Caspase-8 通过裂解至少一种胞质底物间接促进细胞色素 c 的释放。 Bcl-2 仅在最低 caspase-8 浓度下阻断细胞凋亡，这可能解释了为什么 CD95 诱导的细胞凋亡通常可以逃避 Bcl-2 的抑制。
Apoptosis often involves the release of cytochrome c from mitochondria, leading to caspase activation. However, in apoptosis mediated by CD95 (Fas/APO-1), caspase-8 (FLICE/MACH/Mch5) is immediately activated and, in principle, could process other caspases directly. To investigate whether caspase-8 could also act through mitochondria, we added active caspase-8 to a Xenopus cell-free system requiring these organelles. Caspase-8 rapidly promoted the apoptotic program, culminating in fragmentation of chromatin and the nuclear membrane. In extracts devoid of mitochondria, caspase-8 produced DNA degradation, but left nuclear membranes intact. Thus, mitochondria were required for complete engagement of the apoptotic machinery. In the absence of mitochondria, high concentrations of caspase-8 were required to activate downstream caspases. However, when mitochondria were present, the effects of low concentrations of caspase-8 were vastly amplified through cytochrome c-dependent caspase activation. Caspase-8 promoted cytochrome c release indirectly, by cleaving at least one cytosolic substrate. Bcl-2 blocked apoptosis only at the lowest caspase-8 concentrations, potentially explaining why CD95-induced apoptosis can often evade inhibition by Bcl-2.