Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS
Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS
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DOI：
10.1016/s0042-6822(02)00127-7
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发表时间：
2003-03-15
期刊：
影响因子：
3.7
通讯作者：
Krug, RM
中科院分区：
文献类型：
--
作者：
Noah, DL;Twu, KY;Krug, RM
甲型流感病毒NS I蛋白（NS IA蛋白）结合并抑制CPSF的30-kDa亚基的功能，CPSF是细胞前mRNA的3 '末端加工所需的细胞因子。在这里，我们产生了一个重组流感A/Udorn/72病毒编码的NS 1A蛋白含有突变的结合位点的30 kDa亚基的CPSF。该突变病毒基本上减毒，表明NS 1A蛋白中的该结合位点是有效病毒复制所需的。使用这种突变的病毒，我们表明，NS 1A结合CPSF介导的病毒转录后对抗最初的细胞抗病毒反应-干扰素-α/β（IFN-α/β）-独立激活的细胞抗病毒基因的转录，这需要干扰素调节因子-3（IRF-3）的转录因子，被激活的病毒感染。尽管这些细胞抗病毒前mRNA的转录后加工在被野生型甲型流感病毒感染的细胞中被抑制，但功能性抗病毒mRNA在被突变病毒感染的细胞中产生。这些结果证实30-kDa CPSF与NS 1A蛋白的结合在很大程度上负责这些细胞抗病毒前体mRNA的加工的后转录抑制。NS 1A蛋白中该结合位点的突变也影响第二种细胞抗病毒反应：在被突变病毒感染的细胞中，IFN-β mRNA产生得更早且量更大。(C)2003 Elsevier Science（美国）。All rights reserved.
The influenza A virus NS I protein (NS I A protein) binds and inhibits the function of the 30-kDa subunit of CPSF, a cellular factor that is required for the 3'-end processing of cellular pre-mRNAs. Here we generate a recombinant influenza A/Udorn/72 virus that encodes an NS1A protein containing a mutated binding site for the 30-kDa subunit of CPSF. This mutant virus is substantially attenuated, indicating that this binding site in the NS1A protein is required for efficient virus replication. Using this mutant virus, we show that NS1A binding to CPSF mediates the viral posttranscriptional countermeasure against the initial cellular antiviral response-the interferon-alpha/beta (IFN-alpha/beta)-independent activation of the transcription of cellular antiviral genes, which requires the interferon regulatory factor-3 (IRF-3) transcription factor that is activated by virus infection. Whereas the posttranscriptional processing of these cellular antiviral pre-mRNAs is inhibited in cells infected by wild-type influenza A virus, functional antiviral mRNAs are produced in cells infected by the mutant virus. These results establish that the binding of 30-kDa CPSF to the NS 1 A protein is largely responsible for the posuranscriptional inhibition of the processing of these cellular antiviral pre-mRNAs. Mutation of this binding site in the NS 1 A protein also affects a second cellular antiviral response: in cells infected by the mutant virus, IFN-beta mRNA is produced earlier and in larger amounts. (C) 2003 Elsevier Science (USA). All rights reserved.