Identification of Amino Acid Residues Responsible for Inhibition of Host Gene Expression by Influenza A H9N2 NS1 Targeting of CPSF30.
Identification of Amino Acid Residues Responsible for Inhibition of Host Gene Expression by Influenza A H9N2 NS1 Targeting of CPSF30.
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DOI：
10.3389/fmicb.2018.02546
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发表时间：
2018
影响因子：
5.2
通讯作者：
Martinez-Sobrido L
中科院分区：
文献类型：
--
作者：
Rodriguez L;Nogales A;Iqbal M;Perez DR;Martinez-Sobrido L
H9N2甲型流感病毒（IAV）被认为是低致病性禽流感病毒（LPAIV）。这些病毒在亚洲、中东和非洲部分地区许多国家的家禽中流行。在人类和猪中发生的几例h9n2相关感染病例使世界卫生组织（世卫组织）将这些病毒列入具有大流行潜力的病毒之列。迄今为止，哺乳动物适应H9N2病毒的相关过程和机制尚不清楚。来自IAV的非结构蛋白1 （NS1）是一种对抗先天免疫反应的毒力因子。本研究评估了A/鹌鹑/香港/G1/97 (HK/97) H9N2中NS1蛋白抑制宿主免疫应答的能力。我们发现HK/97 NS1蛋白可以抵消干扰素（IFN）的反应，但不能抑制人或禽细胞中宿主基因的表达。相比之下，来自早期H9N2 IAV毒株的NS1蛋白，包括第一株H9N2 A/turkey/Wisconsin/1/1966 (WI/66)，能够抑制IFN和宿主基因的表达。通过WI/66与HK/97 NS1蛋白的嵌合构建，我们确定了参与抑制宿主基因表达的区域和氨基酸残基。HK/97 NS1中的L103F、I106M、P114S、G125D和N139D的氨基酸替换导致与切割和聚腺苷化特异性因子（CPSF30）的30 kda亚基结合，从而抑制宿主基因的表达。值得注意的是，相同氨基酸残基的变化导致WI/66 NS1对宿主基因表达缺乏抑制。重要的是，我们的研究结果确定了NS1与CPSF30结合并抑制宿主基因表达所需的氨基酸的新组合。这些结果也证实了先前的研究表明，NS1蛋白抑制宿主基因表达的能力存在菌株特异性差异。
H9N2 influenza A viruses (IAV) are considered low pathogenic avian influenza viruses (LPAIV). These viruses are endemic in poultry in many countries in Asia, the Middle East and parts of Africa. Several cases of H9N2-associated infections in humans as well as in pigs have led the World Health Organization (WHO) to include these viruses among those with pandemic potential. To date, the processes and mechanisms associated with H9N2 IAV adaptation to mammals are poorly understood. The non-structural protein 1 (NS1) from IAV is a virulence factor that counteracts the innate immune responses. Here, we evaluated the ability of the NS1 protein from A/quail/Hong Kong/G1/97 (HK/97) H9N2 to inhibit host immune responses. We found that HK/97 NS1 protein counteracted interferon (IFN) responses but was not able to inhibit host gene expression in human or avian cells. In contrast, the NS1 protein from earlier H9N2 IAV strains, including the first H9N2 A/turkey/Wisconsin/1/1966 (WI/66), were able to inhibit both IFN and host gene expression. Using chimeric constructs between WI/66 and HK/97 NS1 proteins, we identified the region and amino acid residues involved in inhibition of host gene expression. Amino acid substitutions L103F, I106M, P114S, G125D and N139D in HK/97 NS1 resulted in binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30) and, in consequence, inhibition of host gene expression. Notably, changes in the same amino acid residues resulted in the lack of inhibition of host gene expression by WI/66 NS1. Importantly, our results identified a new combination of amino acids required for NS1 binding to CPSF30 and inhibition of host gene expression. These results also confirm previous studies demonstrating strain specific differences in the ability of NS1 proteins to inhibit host gene expression.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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