The major apoptotic pathway activated and suppressed by poliovirus
The major apoptotic pathway activated and suppressed by poliovirus
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DOI：
10.1128/jvi.77.1.45-56.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Agol, VI
中科院分区：
文献类型：
--
作者：
Belov, GA;Romanova, LI;Agol, VI
细胞对脊髓灰质炎病毒感染的反应是启动凋亡程序，而该程序的实施通常被病毒的抗凋亡功能所抑制。在这里，我们发现脊髓灰质炎病毒感染HeLa细胞或MCF-7细胞的衍生细胞伴随着细胞色素c从线粒体外流。这种外流既发生在流产感染(例如，被盐酸胍中断并以细胞凋亡结束)和产生性感染(导致细胞病变)期间。前一种类型的感染，而不是后一种，伴随着促凋亡蛋白BID的截断。病毒诱导的细胞色素c外流受Bcl2过表达的抑制。Western blotting显示，流产感染和生殖性感染都导致前天冬氨酸蛋白酶-9水平降低。在前一种情况下，这种减少伴随着一种具有活性caspase-9的电泳迁移率的蛋白质的积累。相比之下，在高效感染的细胞中，后者蛋白缺失，但可以检测到流动性改变的caspase-9相关多肽。Caspase-9和caspase-3都被证明是病毒诱导的细胞凋亡的重要标志，如染色质凝集、DNA降解和核碎裂。这些结果和其他一些结果表明了以下情况。脊髓灰质炎病毒感染激活了细胞凋亡途径，包括线粒体损伤、细胞色素c外流以及caspase-9和caspase-3的连续激活。凋亡信号似乎被一个包括Bid二级处理的环路放大。然而，在高效感染的细胞中，凋亡程序的实施可能会被病毒的抗凋亡功能所抑制，这些功能作用于细胞色素c外流的下游步骤(S)。这种抑制似乎至少部分是由原天冬氨酸酶-9的异常加工和降解引起的。
Cells respond to poliovirus infection by switching on the apoptotic program, implementation of which is usually suppressed by viral antiapoptotic functions. We show here that poliovirus infection of HeLa cells or derivatives of MCF-7 cells was accompanied by the efflux of cytochrome c from mitochondria. This efflux occurred during both abortive infection (e.g., interrupted by guanidine-HCl and ending with apoptosis) and productive infection (leading to cytopathic effect). The former type of infection, but not the latter, was accompanied by truncation of the proapoptotic protein Bid. The virus-triggered cytochrome c efflux was suppressed by overexpression of Bcl-2. Both abortive and productive infections also resulted in a decreased level of procaspase-9, as revealed by Western blotting. In the former case, this decrease was accompanied by the accumulation of a protein with the electrophoretic mobility of active caspase-9. In contrast, in the productively infected cells, the latter protein was absent but caspase-9-related polypeptides with altered mobility could be detected. Both caspase-9 and caspase-3 were shown to be essential for the development of such hallmarks of virus-induced apoptosis as chromatin condensation, DNA degradation, and nuclear fragmentation. These and some other results suggest the following scenario. Poliovirus infection activates the apoptotic pathway, involving mitochondrial damage, cytochrome c efflux, and consecutive activation of caspase-9 and caspase-3. The apoptotic signal appears to be amplified by a loop which includes secondary processing of Bid. The implementation of the apoptotic program in productively infected cells may be suppressed, however, by the viral antiapoptotic functions, which act at a step(s) downstream of the cytochrome c efflux. The suppression appears to be caused, at least in part, by aberrant processing and degradation of procaspase-9.