Viperin, MTAP44, and Protein Kinase R Contribute to the Interferon-Induced Inhibition of Bunyamwera Orthobunyavirus Replication
Viperin, MTAP44, and Protein Kinase R Contribute to the Interferon-Induced Inhibition of Bunyamwera Orthobunyavirus Replication
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DOI：
10.1128/jvi.01773-12
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发表时间：
2012-11-01
影响因子：
5.4
通讯作者：
Elliott, Richard M.
中科院分区：
文献类型：
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作者：
Carlton-Smith, Charles;Elliott, Richard M.
抗病毒感染的第一道防线是干扰素（IFN）反应，其在数百种具有假定抗病毒活性的蛋白质的表达中达到高潮，并且必须被病毒克服才能成功复制。非结构性NSs蛋白是布尼亚病毒科（Bunyaviridae）和正布尼亚病毒属（Orthobunyavirus genus）的原型布尼亚病毒（Bunyamwera virus，BUNV）编码的主要IFN拮抗剂。NS蛋白干扰RNA聚合酶II介导的转录，从而抑制细胞mRNA的产生，包括IFN mRNA。不能表达NS蛋白的重组病毒rBUNdelNS不抑制细胞转录，并且是强IFN诱导剂。我们在此报道，通过IFN-β处理刺激进入抗病毒状态的细胞被保护免受野生型BUNV和rBUNdelNSs感染，但感染后加入IFN-β对任一病毒的复制周期几乎没有影响。通过筛选一组过表达单个IFN刺激基因的细胞系，我们发现蛋白激酶R（PKR），MTAP 44，特别是蝰蛇蛋白明显限制BUNV复制。PKR和蝰蛇素的抑制活性需要酶活性。两者合计，我们的数据表明，由IFN介导的BUNV复制的限制是至少三个IFN刺激的基因，可能作用于病毒复制周期的不同阶段的累积效应。
The first line of defense against viral infection is the interferon (IFN) response, which culminates in the expression of hundreds of proteins with presumed antiviral activity, and must be overcome by a virus for successful replication. The nonstructural NSs protein is the primary IFN antagonist encoded by Bunyamwera virus (BUNV), the prototype of the Orthobunyavirus genus and the family Bunyaviridae. The NSs protein interferes with RNA polymerase II-mediated transcription, thereby inhibiting cellular mRNA production, including IFN mRNAs. A recombinant virus, rBUNdelNSs, that is unable to express the NSs protein does not inhibit cellular transcription and is a strong IFN inducer. We report here that cells stimulated into the antiviral state by IFN-beta treatment were protected against wild-type BUNV and rBUNdelNSs infection but addition of IFN-beta after infection had little effect on the replication cycle of either virus. By screening a panel of cell lines that overexpressed individual IFN-stimulated genes, we found that protein kinase R (PKR), MTAP44, and particularly viperin appreciably restricted BUNV replication. The enzymatic activities of PKR and viperin were required for their inhibitory activities. Taken together, our data show that the restriction of BUNV replication mediated by IFN is an accumulated effect of at least three IFN-stimulated genes that probably act on different stages of the viral replication cycle.