NSs Protein of Rift Valley Fever Virus Induces the Specific Degradation of the Double-Stranded RNA-Dependent Protein Kinase
NSs Protein of Rift Valley Fever Virus Induces the Specific Degradation of the Double-Stranded RNA-Dependent Protein Kinase
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DOI：
10.1128/jvi.02148-08
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发表时间：
2009-05-01
影响因子：
5.4
通讯作者：
Weber, Friedemann
中科院分区：
文献类型：
--
作者：
Habjan, Matthias;Pichlmair, Andreas;Weber, Friedemann
裂谷热病毒（RVFV）继续在非洲、沙特阿拉伯和也门的人类和家养动物中引起大规模急性发热和往往致命的疾病。这种布尼亚病毒的高致病性主要是由于病毒蛋白NS，其显示出阻止抗病毒活性I型干扰素（α/β干扰素[IFN-α/β]）的转录诱导。缺乏NS基因的病毒诱导IFN的合成，因此被减毒，而非诱导野生型RVFV株只能通过用IFN预处理来抑制。我们在这里证明，在体外和体内IFN对RVFV的抗病毒活性的很大一部分是由于双链RNA依赖性蛋白激酶（PKR）。然而，PKR介导的病毒抑制对于NS缺失的菌株克隆13比NS表达菌株ZH548明显得多。在体内，克隆13是非致病性的野生型（wt）小鼠，但可以恢复致病性，如果小鼠缺乏PKR基因。相反，ZH548不加区别地杀死wt和PKR敲除小鼠。ZH548对PKR的抗病毒特性具有很大的抗性，因为RVFV NS通过蛋白酶体触发PKR的特异性降解。相比之下，相关但毒性较小的白蛉热西西里病毒和拉克罗斯病毒的NS蛋白尽管是IFN诱导的有效抑制剂，但没有这种抗PKR活性。我们的数据表明，RVFV NS已经获得了额外的抗IFN功能，这可能解释了这种病毒的非凡的致病性。
Rift Valley fever virus (RVFV) continues to cause large outbreaks of acute febrile and often fatal illness among humans and domesticated animals in Africa, Saudi Arabia, and Yemen. The high pathogenicity of this bunyavirus is mainly due to the viral protein NSs, which was shown to prevent transcriptional induction of the antivirally active type I interferons (alpha/beta interferon [ IFN-alpha/beta]). Viruses lacking the NSs gene induce synthesis of IFNs and are therefore attenuated, whereas the noninducing wild-type RVFV strains can only be inhibited by pretreatment with IFN. We demonstrate here in vitro and in vivo that a substantial part of the antiviral activity of IFN against RVFV is due to a double-stranded RNA-dependent protein kinase (PKR). PKR-mediated virus inhibition, however, was much more pronounced for the strain Clone 13 with NSs deleted than for the NSs-expressing strain ZH548. In vivo, Clone 13 was nonpathogenic for wild-type (wt) mice but could regain pathogenicity if mice lacked the PKR gene. ZH548, in contrast, killed both wt and PKR knockout mice indiscriminately. ZH548 was largely resistant to the antiviral properties of PKR because RVFV NSs triggered the specific degradation of PKR via the proteasome. The NSs proteins of the related but less virulent sandfly fever Sicilian virus and La Crosse virus, in contrast, had no such anti-PKR activity despite being efficient suppressors of IFN induction. Our data suggest that RVFV NSs has gained an additional anti-IFN function that may explain the extraordinary pathogenicity of this virus.