Wurzer Walter J, Planz Oliver, Ehrhardt Christina, Giner Martin, Silberzahn Tobias, Pleschka Stephan, Ludwig Stephan
Institute of Molecular Medicine (IMM), Heinrich-Heine Universität, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
EMBO J. 2003 Jun 2;22(11):2717-28. doi: 10.1093/emboj/cdg279.
Apoptosis is a hallmark event observed upon infection with many viral pathogens, including influenza A virus. The apoptotic process is executed by a proteolytic system consisting of a family of cysteinyl proteases, termed caspases. Since the consequences of apoptosis induction and caspase activation for the outcome of an influenza virus infection are not clear, we have addressed this issue by interfering with expression or function of a major virus-induced apoptosis effector, caspase 3. Surprisingly, influenza virus propagation was strongly impaired in the presence of an inhibitor that blocks caspase 3 and in cells where caspase 3 was partially knocked down by small interfering RNAs. Consistent with these findings, poor replication efficiencies of influenza A viruses in cells deficient for caspase 3 could be boosted 30-fold by ectopic expression of the protein. Mechanistically, the block in virus propagation appeared to be due to retention of the viral RNP complexes in the nucleus, preventing formation of progeny virus particles. Our findings indicate that caspase 3 activation during the onset of apoptosis is a crucial event for efficient influenza virus propagation.
细胞凋亡是在感染包括甲型流感病毒在内的多种病毒病原体时观察到的标志性事件。细胞凋亡过程由一个由半胱氨酸蛋白酶家族（即胱天蛋白酶）组成的蛋白水解系统执行。由于细胞凋亡诱导和胱天蛋白酶激活对流感病毒感染结果的影响尚不清楚，我们通过干扰主要的病毒诱导的细胞凋亡效应因子胱天蛋白酶3的表达或功能来解决这个问题。令人惊讶的是，在存在阻断胱天蛋白酶3的抑制剂的情况下以及在胱天蛋白酶3被小干扰RNA部分敲低的细胞中，流感病毒的增殖受到强烈损害。与这些发现一致，甲型流感病毒在缺乏胱天蛋白酶3的细胞中的低复制效率可通过该蛋白的异位表达提高30倍。从机制上讲，病毒增殖受阻似乎是由于病毒核糖核蛋白复合物滞留在细胞核中，阻止了子代病毒颗粒的形成。我们的研究结果表明，细胞凋亡开始时胱天蛋白酶3的激活是流感病毒高效增殖的关键事件。
