Herpes simplex virus 1 blocks caspase-3-independent and caspase-dependent pathways to cell death
Herpes simplex virus 1 blocks caspase-3-independent and caspase-dependent pathways to cell death
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DOI：
10.1128/jvi.73.4.3219-3226.1999
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发表时间：
1999-04-01
影响因子：
5.4
通讯作者：
Roizman, B
中科院分区：
文献类型：
--
作者：
Galvan, V;Brandimarti, R;Roizman, B
早期的报道表明，单纯疱疹病毒1型(HSV-1)突变株可诱导细胞程序性死亡，野生型HSV可阻断由病毒基因产物、免疫系统效应器(如Fas和肿瘤坏死因子途径)或非特异性应激剂(如山梨醇或热休克)触发的细胞死亡程序的执行。该实验室的一份报告显示，半胱氨酸酶抑制剂不能阻止感染HSV-1D120突变株引起的DNA片段化。为了确定HSV-1诱导和阻断细胞程序性死亡的事件，我们检查了感染野生型病毒或D120突变体的细胞或感染并暴露于山梨醇的细胞。我们报道：(1)尽管HSV-1D120突变株引起线粒体膜细胞色素c的释放和线粒体膜的去极化，但由于caspase 3不被激活，DNA片段化也不被caspase抑制剂阻断，HSV-1 D120突变株通过caspase-3非激活的途径诱导细胞凋亡。(Ii)感染野生型HSV-1的细胞没有表现出与这些研究中检测的程序性细胞死亡有关的症状。(3)细胞色素c释放，线粒体内电位丧失，caspase-3激活，染色体DNA片段化，暴露于渗透性休克的未感染细胞发生caspase依赖的细胞凋亡。(4)尽管野生型HSV-1感染细胞并暴露于山梨醇后caspase-3被激活，但细胞色素c外流、线粒体膜去极化和DNA片段化被阻断。我们认为，虽然D120通过caspase-3非依赖途径诱导细胞凋亡，但野生型病毒阻断了该途径诱导的细胞凋亡，也阻断了渗透性休克诱导的caspase依赖途径。Caspase依赖途径的阻断可能发生在caspase-3激活的下游。
Earlier reports have shown that herpes simplex virus 1 (HSV-1) mutants induce programmed cell death and that wild-type HSV blocks the execution of the cell death program triggered by viral gene products, by the effecters of the immune system such as the Fas and tumor necrosis factor pathways, or by nonspecific stress agents such as either osmotic shock induced by sorbitol or thermal shock. A report from this laboratory showed that caspase inhibitors do not block DNA fragmentation induced by infection with the HSV-1 d120 mutant. To identify the events in programmed cell death induced and blocked by HSV-1, we examined cells infected with wild-type virus or the d120 mutant or cells infected and exposed to sorbitol. We report that: (i) the HSV-1 d120 mutant induced apoptosis by a caspase-3-independent pathway inasmuch as caspase 3 was not activated and DNA fragmentation was not blocked by caspase inhibitors even though the virus caused cytochrome c release and depolarization of the inner mitochondrial membrane. (ii) Cells infected with wild-type HSV-1 exhibited none of the manifestations associated with programmed cell death assayed in these studies. (iii) Uninfected cells exposed to osmotic shock succumbed to caspase-dependent apoptosis inasmuch as cytochrome c was released, the inner mitochondrial potential was lost, caspase-3 was activated, and chromosomal DNA was fragmented. (iv) Although caspase-3 was activated in cells infected with wild-type HSV-1 and exposed to sorbitol, cytochrome c outflow, depolarization of the inner mitochondrial membrane, and DNA fragmentation were blocked. We conclude that although d120 induces apoptosis by a caspase-3-independent pathway, the wild-type virus blocks apoptosis induced by this pathway and also blocks the caspase-dependent pathway induced by osmotic shock. The block in the caspase-dependent pathway may occur downstream of caspase-3 activation.