Vesicular stomatitis viruses expressing wild-type or mutant M proteins activate apoptosis through distinct pathways
Vesicular stomatitis viruses expressing wild-type or mutant M proteins activate apoptosis through distinct pathways
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DOI：
10.1128/jvi.79.7.4170-4179.2005
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Lyles, DS
中科院分区：
文献类型：
--
作者：
Gaddy, DF;Lyles, DS
水泡性口炎病毒（VSV）至少通过两种机制诱导细胞凋亡。病毒基质（M）蛋白由于抑制宿主基因表达而经由线粒体途径诱导细胞凋亡。然而，在某些细胞类型中，表达野生型（wt）M蛋白的VSV对宿主基因表达的抑制延迟了VSV诱导的细胞凋亡，表明涉及另一种机制。为了支持这一点，重组M51 R-M（rM 51 R-M）病毒，表达突变体M蛋白，这是在其抑制宿主基因表达的能力有缺陷，诱导细胞凋亡更迅速地在L929细胞比表达野生型M蛋白的病毒。在这里，我们确定的caspase途径，rM 51 R-M病毒诱导细胞凋亡。半胱天冬酶活性的分析，使用荧光半胱天冬酶测定和蛋白质印迹法，表明，每个主要的引发剂半胱天冬酶，半胱天冬酶-8，半胱天冬酶-9，和半胱天冬酶-12，被激活的rIW 51 R-M病毒感染期间。Bcl-2（一种线粒体途径的抑制剂）或法师-3（一种caspase-12激活的抑制剂）的过表达并不延迟rM 51 R-M病毒感染的L929细胞的凋亡诱导。然而，caspase-8活性抑制剂显著延迟凋亡诱导。此外，半胱天冬酶-8活性的抑制阻止了半胱天冬酶-9的活化，表明半胱天冬酶-9通过与半胱天冬酶-8的串扰而活化。这些数据表明，表达突变M蛋白的VSV通过死亡受体凋亡途径诱导凋亡，这是一种与表达wt M蛋白的VSV诱导的机制不同的机制。
Vesicular stomatitis virus (VSV) induces apoptosis by at least two mechanisms. The viral matrix (M) protein induces apoptosis via the mitochondrial pathway due to the inhibition of host gene expression. However, in some cell types, the inhibition of host gene expression by VSV expressing wild-type (wt) M protein delays VSV-induced apoptosis, indicating that another mechanism is involved. In support of this, the recombinant M51R-M (rM51R-M) virus, expressing a mutant M protein that is defective in its ability to inhibit host gene expression, induces apoptosis much more rapidly in L929 cells than do viruses expressing wt M protein. Here, we determine the caspase pathways by which the rM51R-M virus induces apoptosis. An analysis of caspase activity, using fluorometric caspase assays and Western blots, indicated that each of the main initiator caspases, caspase-8, caspase-9, and caspase-12, were activated during infection with the rIW51R-M virus. The overexpression of Bcl-2, an inhibitor of the mitochondrial pathway, or MAGE-3, an inhibitor of caspase-12 activation, did not delay apoptosis induction in rM51R-M virus-infected L929 cells. However, an inhibitor of caspase-8 activity significantly delayed apoptosis induction. Furthermore, the inhibition of caspase-8 activity prevented the activation of caspase-9, suggesting that caspase-9 is activated by cross talk with caspase-8. These data indicate that VSV expressing the mutant M protein induces apoptosis via the death receptor apoptotic pathway, a mechanism distinct from that induced by VSV expressing the wt M protein.