Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza a virus
Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza a virus
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DOI：
10.1128/jvi.01265-06
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发表时间：
2007-01-01
影响因子：
5.4
通讯作者：
Garcia-Sastre, Adolfo
中科院分区：
文献类型：
--
作者：
Mibayashi, Masaki;Martinez-Sobrido, Luis;Garcia-Sastre, Adolfo
视黄酸诱导基因I产物(RIG-I)被认为是RNA病毒感染导致β-干扰素(IFN-β)诱导的细胞传感器。然而，已知许多病毒编码的病毒产物会抑制干扰素-β的产生。在甲型流感病毒中，病毒非结构蛋白1(NS1)通过抑制参与干扰素-β转录激活的转录因子(包括Iry-3)的激活来阻止干扰素-β启动子的诱导。NS1的抑制特性似乎至少部分是由于它与双链RNA(DsRNA)结合，导致这种RIG-I激活的病毒媒介被隔离。然而，NS1在Rig-I介导的干扰素-β诱导中的确切作用还没有被表征。我们现在报道，甲型流感病毒的NS1与RIG-I相互作用，并抑制RIG-I介导的干扰素-β的诱导。即使当结构性激活的突变RIG-I(在没有dsRNA的情况下)被用来触发干扰素-β的产生时，这种抑制也是明显的。RIG-I、其下游信号伙伴IPS-1和NS1的共表达导致细胞裂解后富含IPS-1的抗增溶部分中RIG-I和NS1水平的增加。这些结果表明RIG-I、IPS-1和NS1成为同一复合体的一部分。与这一观点一致的是，NS1还被发现通过过表达IPS-1来抑制干扰素-β启动子的激活。我们的结果表明，除了隔离dsRNA外，甲型流感病毒的NS1还与RIG-I结合，抑制IRF-3的下游激活，阻止干扰素-β的转录诱导。
The retinoic acid-inducible gene I product (RIG-I) has been identified as a cellular sensor of RNA virus infection resulting in beta interferon (IFN-beta) induction. However, many viruses are known to encode viral products that inhibit IFN-beta production. In the case of influenza A virus, the viral nonstructural protein 1 (NS1) prevents the induction of the IFN-beta promoter by inhibiting the activation of transcription factors, including IRY-3, involved in IFN-beta transcriptional activation. The inhibitory properties of NS1 appear to be due at least in part to its binding to double-stranded RNA (dsRNA), resulting in the sequestration of this viral mediator of RIG-I activation. However, the precise effects of NS1 on the RIG-I-mediated induction of IFN-beta have not been characterized. We now report that the NS1 of influenza A virus interacts with RIG-I and inhibits the RIG-I-mediated induction of IFN-beta. This inhibition was apparent even when a mutant RIG-I that is constitutively activated (in the absence of dsRNA) was used to trigger IFN-beta production. Coexpression of RIG-I, its downstream signaling partner, IPS-1, and NS1 resulted in increased levels of RIG-I and NS1 within an IPS-1-rich, solubilization-resistant fraction after cell lysis. These results suggest that RIG-I, IPS-1, and NS1 become part of the same complex. Consistent with this idea, NS1 was also found to inhibit IFN-beta promoter activation by IPS-1 overexpression. Our results indicate that, in addition to sequestering dsRNA, the NS1 of influenza A virus binds to RIG-I and inhibits downstream activation of IRF-3, preventing the transcriptional induction of IFN-beta.