Bitzer Michael, Armeanu Sorin, Prinz Florian, Ungerechts Guy, Wybranietz Wolfgang, Spiegel Martin, Bernlöhr Christian, Cecconi Francesco, Gregor Michael, Neubert Wolfgang J, Schulze-Osthoff Klaus, Lauer Ulrich M
Department of Internal Medicine I, University Clinic Tübingen, D-72076 Tübingen, Germany.
J Biol Chem. 2002 Aug 16;277(33):29817-24. doi: 10.1074/jbc.M111898200. Epub 2002 May 20.
Apoptotic cell death is of central importance in the pathogenesis of viral infections. Activation of a cascade of cysteine proteases, i.e. caspases, plays a key role in the effector phase of virus-induced apoptosis. However, little is known about pathways leading to the activation of initiator caspases in virus-infected host cells. Recently, we have shown that Sendai virus (SeV) infection triggers apoptotic cell death by activation of the effector caspase-3 and initiator caspase-8. We now investigated mechanisms leading to the activation of another initiator caspase, caspase-9. Unexpectedly we found that caspase-9 cleavage is not dependent on the presence of active caspases-3 or -8. Furthermore, the presence of caspase-9 in mouse embryonic fibroblast (MEF) cells was a prerequisite for Sendai virus-induced apoptotic cell death. Caspase-9 activation occurred without the release of cytochrome c from mitochondria and was not dependent on the presence of Apaf-1 or reactive oxygen intermediates. Our results therefore suggest an alternative mechanism for caspase-9 activation in virally infected cells beside the well characterized pathways via death receptors or mitochondrial cytochrome c release.
凋亡性细胞死亡在病毒感染的发病机制中至关重要。一系列半胱氨酸蛋白酶（即胱天蛋白酶）的激活在病毒诱导的凋亡效应阶段起着关键作用。然而，对于病毒感染的宿主细胞中起始胱天蛋白酶激活的途径知之甚少。最近，我们发现仙台病毒（SeV）感染通过激活效应胱天蛋白酶-3和起始胱天蛋白酶-8触发凋亡性细胞死亡。我们现在研究了导致另一种起始胱天蛋白酶——胱天蛋白酶-9激活的机制。出乎意料的是，我们发现胱天蛋白酶-9的切割不依赖于活性胱天蛋白酶-3或-8的存在。此外，胱天蛋白酶-9在小鼠胚胎成纤维细胞（MEF）中的存在是仙台病毒诱导凋亡性细胞死亡的先决条件。胱天蛋白酶-9的激活在没有细胞色素c从线粒体释放的情况下发生，并且不依赖于凋亡蛋白酶激活因子-1（Apaf-1）或活性氧中间体的存在。因此，我们的结果表明，在病毒感染的细胞中，除了通过死亡受体或线粒体细胞色素c释放的已明确的途径外，还存在一种胱天蛋白酶-9激活的替代机制。
