Budihardjo I, Oliver H, Lutter M, Luo X, Wang X
Howard Hughes Medical Institute, Dallas, Texas, USA.
Annu Rev Cell Dev Biol. 1999;15:269-90. doi: 10.1146/annurev.cellbio.15.1.269.
Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pathway, activation of caspase-8 following its recruitment to the death-inducing signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various viral and mammalian proteins. Activated caspase-8 can activate downstream caspases by direct cleavage or indirectly by cleaving Bid and inducing cytochrome c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully functional in recruiting and activating procaspase-9. Activated caspase-9 will then cleave and activate downstream caspases such as caspase-3, -6, and -7. This pathway is regulated at several steps, including the release of cytochrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by Apaf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP).
半胱天冬酶激活在细胞凋亡的执行过程中起着核心作用。半胱天冬酶激活的生化途径的关键组成部分最近已被阐明。在本综述中，我们重点关注半胱天冬酶激活的两条研究最为深入的途径：细胞表面死亡受体途径和线粒体起始途径。在细胞表面死亡受体途径中，半胱天冬酶-8被招募到死亡诱导信号复合物（DISC）后被激活，这是传递死亡信号的关键事件。这一事件在几个不同层面受到各种病毒和哺乳动物蛋白的调控。活化的半胱天冬酶-8可以通过直接切割或间接切割Bid并诱导细胞色素c从线粒体释放来激活下游半胱天冬酶。在线粒体起始途径中，半胱天冬酶激活是由多聚体Apaf-1/细胞色素c复合物的形成触发的，该复合物在招募和激活半胱天冬酶原-9方面具有完全功能。活化的半胱天冬酶-9随后将切割并激活下游半胱天冬酶，如半胱天冬酶-3、-6和-7。该途径在几个步骤受到调控，包括细胞色素c从线粒体的释放、Apaf-1对dATP/ATP的结合和水解，以及凋亡抑制蛋白（IAP）家族蛋白对半胱天冬酶激活的抑制。
