Cyclophilin E functions as a negative regulator to influenza virus replication by impairing the formation of the viral ribonucleoprotein complex.
Cyclophilin E functions as a negative regulator to influenza virus replication by impairing the formation of the viral ribonucleoprotein complex.
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亲环蛋白 E 通过损害病毒核糖核蛋白复合物的形成对流感病毒复制发挥负调节作用
DOI：
10.1371/journal.pone.0022625
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Wang Z;Liu X;Zhao Z;Xu C;Zhang K;Chen C;Sun L;Gao GF;Ye X;Liu W
研究背景甲型流感病毒核蛋白（NP）是一种多功能蛋白，在病毒基因组的复制和转录中起着关键作用。因此，研究与NP相互作用的宿主因子可能有助于阐明宿主限制性屏障的机制和甲型流感病毒的组织嗜性。在这里，亲环素E（CypE），肽基丙基顺反异构酶（PPIase）家族的成员，被发现结合到NP和抑制病毒的复制和转录。在本研究中，CypE被发现与NP相互作用，但不与病毒核糖核蛋白复合物（vRNP）的其他组分：PB 1，PB 2和PA相互作用。突变数据显示，CypE结构域由残基137-186组成，负责其与NP的结合。功能分析结果表明CypE是流感病毒生活史中的负调控因子。此外，敲低CypE导致三种类型的病毒RNA水平增加，表明CypE对病毒复制和转录产生负面影响。此外，CypE的上调抑制流感病毒聚合酶的活性。我们确定CypE负调节流感病毒复制和转录的分子机制是通过干扰NP自缔合和NP-PB 1和NP-PB 2相互作用。CypE是一种宿主限制性因子，通过损害vRNP的形成来抑制NP的功能以及病毒的复制和转录。这些数据将有助于我们更好地了解甲型流感病毒的宿主限制性屏障、宿主适应性和组织嗜性的分子机制。
Background The nucleoprotein (NP) of influenza A virus is a multifunctional protein that plays a critical role in the replication and transcription of the viral genome. Therefore, examining host factors that interact with NP may shed light on the mechanism of host restriction barriers and the tissue tropism of influenza A virus. Here, Cyclophilin E (CypE), a member of the peptidyl-propyl cis-trans isomerase (PPIase) family, was found to bind to NP and inhibit viral replication and transcription. Methodology/Principal Findings In the present study, CypE was found to interact with NP but not with the other components of the viral ribonucleoprotein complex (vRNP): PB1, PB2, and PA. Mutagenesis data revealed that the CypE domain comprised of residues 137–186 is responsible for its binding to NP. Functional analysis results indicated that CypE is a negative regulator in the influenza virus life cycle. Furthermore, knock-down of CypE resulted in increased levels of three types of viral RNA, suggesting that CypE negatively affects viral replication and transcription. Moreover, up-regulation of CypE inhibited the activity of influenza viral polymerase. We determined that the molecular mechanism by which CypE negatively regulates influenza virus replication and transcription is by interfering with NP self-association and the NP-PB1 and NP-PB2 interactions. Conclusions/Significance CypE is a host restriction factor that inhibits the functions of NP, as well as viral replication and transcription, by impairing the formation of the vRNP. The data presented here will help us to better understand the molecular mechanisms of host restriction barriers, host adaptation, and tissue tropism of influenza A virus.
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