Nuclear Envelope Disruption Involving Host Caspases Plays a Role in the Parvovirus Replication Cycle
Nuclear Envelope Disruption Involving Host Caspases Plays a Role in the Parvovirus Replication Cycle
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DOI：
10.1128/jvi.01999-10
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Pante, Nelly
中科院分区：
文献类型：
--
作者：
Cohen, Sarah;Marr, Alexandra K.;Pante, Nelly
细小病毒是在宿主细胞核中复制的小的、无包膜的、单链DNA病毒。我们以前已经发现，在感染早期的小鼠细小病毒（MVM）引起小，短暂的破坏核膜（NE）。我们现在已经研究了MVM破坏NE的机制。在这里，我们表明，病毒磷脂酶A2，唯一已知的酶结构域上的细小病毒衣壳，不参与引起NE中断。相反，该病毒利用宿主细胞半胱天冬酶，其是参与在细胞凋亡期间引起NE分解的蛋白酶，以促进这些核膜破坏。药理学抑制剂的研究表明，caspase-3特别是参与。半胱天冬酶-3抑制剂防止核纤层蛋白裂解和NE破坏在MVM感染的小鼠成纤维细胞，并减少核进入MVM衣壳和病毒基因表达。然而，在MVM感染的细胞中，Caspase-3在高于基础水平时不被激活，并且在早期MVM感染期间不触发细胞凋亡的其他方面。相反，具有基础活性的caspase-3被重新定位于感染细胞的细胞核。我们提出，NE中断涉及半胱天冬酶在（i）细小病毒进入细胞核和（ii）改变宿主蛋白质的区室化的方式，这是有利于病毒发挥作用。
Parvoviruses are small, nonenveloped, single-stranded DNA viruses which replicate in the nucleus of the host cell. We have previously found that early during infection the parvovirus minute virus of mice (MVM) causes small, transient disruptions of the nuclear envelope (NE). We have now investigated the mechanism used by MVM to disrupt the NE. Here we show that the viral phospholipase A2, the only known enzymatic domain on the parvovirus capsid, is not involved in causing NE disruption. Instead, the virus utilizes host cell caspases, which are proteases involved in causing NE breakdown during apoptosis, to facilitate these nuclear membrane disruptions. Studies with pharmacological inhibitors indicate that caspase-3 in particular is involved. A caspase-3 inhibitor prevents nuclear lamin cleavage and NE disruption in MVM-infected mouse fibroblast cells and reduces nuclear entry of MVM capsids and viral gene expression. Caspase-3 is, however, not activated above basal levels in MVM-infected cells, and other aspects of apoptosis are not triggered during early MVM infection. Instead, basally active caspase-3 is relocalized to the nuclei of infected cells. We propose that NE disruption involving caspases plays a role in (i) parvovirus entry into the nucleus and (ii) alteration of the compartmentalization of host proteins in a way that is favorable for the virus.