NSs protein of rift valley fever virus blocks interferon production by inhibiting host gene transcription
NSs protein of rift valley fever virus blocks interferon production by inhibiting host gene transcription
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DOI：
10.1128/jvi.78.18.9798-9806.2004
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发表时间：
2004-09-01
影响因子：
5.4
通讯作者：
Haller, O
中科院分区：
文献类型：
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作者：
Billecocq, A;Spiegel, M;Haller, O
裂谷热病毒（RVFV）是非洲动物流行病和流行病的重要原因，也是生物恐怖主义的潜在病原体。鉴于迫切需要抗病毒治疗和安全疫苗，需要更好地了解控制裂谷热病毒毒力和致病性的因素。我们之前已经证明，NSs基因突变的裂谷热病毒毒株是α / β干扰素（ifn - α / β）的优秀诱导剂，并且在小鼠中高度减弱。在这里，我们证明了NSs足以在转录水平上阻断ifn - β基因的表达。在短暂表达NSs的细胞中，ifn - β转录物不能被病毒感染或poly（I:C）转染诱导。具有抗ifn活性的NSs在细胞核中积累。相比之下，失去ifn抑制活性的突变型NSs仍留在细胞质中，表明核定位起作用。IFN的合成受特定转录因子的调控，包括干扰素调节因子（IRF-3）、NF-kappaB和AP-1。在NSs存在的情况下，IRF-3仍然被激活并移动到细胞核。同样，NF-kappaB和AP-1被正常激活，如电泳迁移率转移试验所示。此外，研究还发现NSs可以抑制一个组成启动子的转录活性，这与最近的研究结果一致，即NSs靶向基础细胞转录因子TFIIH。目前的结果表明，与其他病毒IFN拮抗剂不同，NSs不会抑制IFN特异性转录因子，而是在随后的步骤中阻断IFN基因的表达。
Rift Valley fever virus (RVFV) is an important cause of epizootics and epidemics in Africa and a potential agent of bioterrorism. A better understanding of the factors that govern RVFV virulence and pathogenicity is required, given the urgent need for antiviral therapies and safe vaccines. We have previously shown that RVFV strains with mutations in the NSs gene are excellent inducers of alpha/beta interferon (IFN-alpha/beta) and are highly attenuated in mice. Here, we demonstrate that NSs is sufficient to block IFN-beta gene expression at the transcriptional level. In cells transiently expressing NSs, IFN-beta transcripts were not inducible by viral infection or by transfection of poly(I:C). NSs with anti-IFN activity accumulated in the nucleus. In contrast, mutant forms of NSs that had lost their IFN-inhibiting activity remained in the cytoplasm, indicating that nuclear localization plays a role. IFN synthesis is regulated by specific transcription factors, including interferon regulatory factor (IRF-3), NF-kappaB, and AP-1. In the presence of NSs, IRF-3 was still activated and moved to the nucleus. Likewise, NF-kappaB and AP-1 were activated normally, as shown in electrophoretic mobility shift assays. Moreover, NSs was found to inhibit transcriptional activity of a constitutive promoter, in agreement with recent findings showing that NSs targets the basal cellular transcription factor TFIIH. The present results suggest that NSs, unlike other viral IFN antagonists, does not inhibit IFN-specific transcription factors but blocks IFN gene expression at a subsequent step.