Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels
Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels
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DOI：
10.1128/jvi.76.22.11414-11424.2002
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发表时间：
2002-11-01
影响因子：
5.4
通讯作者：
Tyler, KL
中科院分区：
文献类型：
--
作者：
Kominsky, DJ;Bickel, RJ;Tyler, KL
许多病毒属于不同的病毒家族，具有不同的结构和复制策略，在体外培养的细胞和体内的组织中都能诱导细胞凋亡。尽管如此，人们对病毒感染过程中诱导的特定细胞凋亡途径知之甚少。我们先前已经证明，呼肠孤病毒诱导的HEK细胞的凋亡是由死亡受体激活启动的，但需要线粒体凋亡途径来增强其最大表达。我们现在发现呼肠孤病毒感染HEK细胞与线粒体促凋亡因子细胞色素c和Smac/DLABLO的选择性胞浆释放有关，而与凋亡诱导因子的释放无关。这些因子的释放与线粒体跨膜电位的丧失无关，并被Bcl-2的过度表达所阻断。稳定表达caspase-9b是caspase-9的显性-阴性形式，可以阻断呼肠孤病毒诱导的caspase-9的激活，但不能显著减少关键效应因子caspase-3的激活。Smac/Diablo通过对细胞凋亡抑制蛋白(IAPs)的作用促进细胞凋亡。呼肠孤病毒感染与细胞IAP的选择性下调有关，包括c-LAP1、XIAP和Survivin，这些效应被Bcl2的表达所阻断，建立了IAP下调对线粒体事件的依赖。综上所述，这些结果与Smac/DLABLO介导的1APs抑制而不是细胞色素c介导的caspase-9激活是呼肠孤病毒诱导的细胞凋亡中线粒体增强的关键事件的模型是一致的。这些研究首次证明Smac/DIABLO与病毒诱导的细胞凋亡有关。
Many viruses belonging to diverse viral families with differing structure and replication strategies induce apoptosis both in cultured cells in vitro and in tissues in vivo. Despite this fact, little is known about the specific cellular apoptotic pathways induced during viral infection. We have previously shown that reovirus-induced apoptosis of HEK cells is initiated by death receptor activation but requires augmentation by mitochondrial apoptotic pathways for its maximal expression. We now show that reovirus infection of HEK cells is associated with selective cytosollic release of the mitochondrial proapoptotic factors cytochrome c and Smac/DLABLO, but not the release of apoptosis-inducing factor. Release of these factors is not associated with loss of mitochondrial transmembrane potential and is blocked by overexpression of Bcl-2. Stable expression of caspase-9b, a dominant-negative form of caspase-9, blocks reovirus-induced caspase-9 activation but fails to significantly reduce activation of the key effector caspase, caspase-3. Smac/DIABLO enhances apoptosis through its action on cellular inhibitor of apoptosis proteins (IAPs). Reovirus infection is associated with selective downregulation of cellular IAPs, including c-LAP1, XIAP, and survivin, effects that are blocked by Bcl-2 expression, establishing the dependence of IAP down-regulation on mitochondriall events. Taken together, these results are consistent with a model in which Smac/DLABLO-mediated inhibition of 1APs, rather than cytochrome c-mediated activation of caspase-9, is the key event responsible for mitochondrial augmentation of reovirus-induced apoptosis. These studies provide the first evidence for the association of Smac/DIABLO with virus-induced apoptosis.