The proteolytic procaspase activation network:: an in vitro analysis
The proteolytic procaspase activation network:: an in vitro analysis
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DOI：
10.1038/sj.cdd.4400589
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发表时间：
1999-11-01
影响因子：
12.4
通讯作者：
Vandenabeele, P
中科院分区：
文献类型：
--
作者：
Van de Craen, M;Declercq, W;Vandenabeele, P
通常，凋亡刺激导致半胱天冬酶的激活。一旦激活，半胱天冬酶可以诱导涉及其他半胱天冬酶家族成员的蛋白水解激活的细胞内信号传导途径。我们报告了8种小鼠前半胱氨酸蛋白酶的体外加工，它们的酶活性对应物，半胱氨酸蛋白酶-8处理所有的前半胱氨酸蛋白酶检查。半胱天冬酶-1和-11处理效应物半胱天冬酶原-3和-7，并在较小程度上处理半胱天冬酶原-6。然而，反之亦然，没有半胱天冬酶-1样前半胱天冬酶被效应半胱天冬酶激活，这表明半胱天冬酶-1亚家族成员要么在凋亡效应半胱天冬酶的上游起作用，要么是完全独立的激活途径的一部分。胱天蛋白酶-2成熟的胱天蛋白酶-8和-3，并在较小程度上由胱天蛋白酶-7，而活性的胱天蛋白酶-2不处理任何检查的胱天蛋白酶，除了自己的前体。因此，caspase-2可能不能启动广泛的蛋白水解信号级联反应。此外，切割数据不仅揭示了caspase-3和-8，caspase-6和-3，以及caspase-6和-7之间的蛋白水解扩增，而且还揭示了涉及多个激活的caspase的正反馈环。我们的结果表明存在分层的蛋白水解蛋白酶原激活网络，一旦关键的半胱天冬酶被激活，这将导致多个半胱天冬酶活性的显著增加。蛋白水解的半胱氨酸天冬氨酸蛋白酶原激活网络可能允许不同的凋亡刺激导致负责细胞膜、胞质溶胶、细胞器和细胞核的典型过程的底物的特异性裂解，其表征细胞通过凋亡而死亡。
In general, apoptotic stimuli lead to activation of caspases. Once activated, a caspase can induce intracellular signaling pathways involving proteolytic activation of other caspase family members. We report the in vitro processing of eight murine procaspases by their enzymatically active counterparts, Caspase-8 processed all procaspases examined. Caspase-1 and -11 processed the effector caspases procaspase-3 and -7, and to a lesser extent procaspase-6. However, vice versa, none of the caspase-1-like procaspases was activated by the effector caspases, This suggests that the caspase-1 subfamily members either act upstream of the apoptosis effector caspases or else are part of a totally separate activation pathway. Procaspase-2 was maturated by caspase-8 and -3, and to a lesser extent by caspase-7, while the active caspase-2 did not process any of the procaspases examined, except its own precursor. Hence, caspase-2 might not be able to initiate a wide proteolytic signaling cascade, Additionally, cleavage data reveal not only proteolytic amplification between caspase-3 and -8, caspase-6 and -3, and caspase-6 and -7, but also positive feedback loops involving multiple activated caspases, Our results suggest the existence of a hierarchic proteolytic procaspase activation network, which would lead to a dramatic increase in multiple caspase activities once key caspases are activated. The proteolytic procaspase activation network might allow that different apoptotic stimuli result in specific cleavage of substrates responsible for typical processes at the cell membrane, the cytosol, the organelles, and the nucleus, which characterize a cell dying by apoptosis.