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宿主ANP32A介导流感病毒复制酶的组装
2020-11-22 23:43
来源：小柯机器人

英国牛津大学Jonathan M. Grimes、Ervin Fodor等研究人员合作发现，宿主ANP32A介导流感病毒复制酶的组装。2020年11月18日，《自然》杂志在线发表了这项成果。

研究人员表示，水禽是一个巨大的储存库，新的大流行性甲型流感病毒可从中出现。流感病毒包含一个反义的分段RNA基因组，在病毒核糖核蛋白复合体的作用下，该基因组被病毒异三聚体RNA聚合酶（FluPol）转录和复制。禽流感A病毒（FluPolA）的RNA聚合酶在人类细胞中无法有效复制病毒RNA，因为酸性核磷酸蛋白32（ANP32）是FluPol活性的必需宿主蛋白家族中特定物种的差异。宿主适应性突变，特别是PB2亚基627结构域中第627位氨基酸残基处的谷氨酸到赖氨酸突变，禽流感FluPolA可以克服这一限制并在人ANP32存在的情况下有效复制病毒RNA蛋白质。但是，基因组复制的分子机制以及与ANP32蛋白的相互作用仍是未知之数。
 
研究人员报道了与人和鸡ANP32A复合的C型流感病毒聚合酶（FluPolC）冷冻电镜结构。在这两种结构中，两个FluPolC分子形成一个不对称的二聚体，由ANP32A的N端富含亮氨酸的重复结构域桥接。ANP32A的C端低复杂性酸性区域插入不对称FluPolA二聚体的两个并列的PB2 627结构域之间，这提示了一种自适应PB2（E627K）突变如何使病毒RNA在哺乳动物宿主中复制的机制。研究人员认为，该复合物是病毒RNA基因组的复制平台，其中一个FluPol分子充当复制酶，而另一个则将新生复制产物组装成病毒核糖核蛋白复合物。
 
附：英文原文

Title: Host ANP32A mediates the assembly of the influenza virus replicase

Author: Loc Carrique, Haitian Fan, Alexander P. Walker, Jeremy R. Keown, Jane Sharps, Ecco Staller, Wendy S. Barclay, Ervin Fodor, Jonathan M. Grimes

Issue&Volume: 2020-11-18

Abstract: Aquatic birds represent a vast reservoir from which new pandemic influenza A viruses can emerge1. Influenza viruses contain a negative-sense segmented RNA genome that is transcribed and replicated by the viral heterotrimeric RNA polymerase (FluPol) in the context of viral ribonucleoprotein complexes2,3. RNA polymerases of avian influenza A viruses (FluPolA) replicate viral RNA inefficiently in human cells because of species-specific differences in acidic nuclear phosphoprotein 32 (ANP32), a family of essential host proteins for FluPol activity4. Host-adaptive mutations, particularly a glutamic-acid-to-lysine mutation at amino acid residue 627 (E627K) in the 627 domain of the PB2 subunit, enable avian FluPolA to overcome this restriction and efficiently replicate viral RNA in the presence of human ANP32 proteins. However, the molecular mechanisms of genome replication and the interplay with ANP32 proteins remain largely unknown. Here we report cryo-electron microscopy structures of influenza C virus polymerase (FluPolC) in complex with human and chicken ANP32A. In both structures, two FluPolC molecules form an asymmetric dimer bridged by the N-terminal leucine-rich repeat domain of ANP32A. The C-terminal low-complexity acidic region of ANP32A inserts between the two juxtaposed PB2 627 domains of the asymmetric FluPolA dimer, suggesting a mechanism for how the adaptive PB2(E627K) mutation enables the replication of viral RNA in mammalian hosts. We propose that this complex represents a replication platform for the viral RNA genome, in which one of the FluPol molecules acts as a replicase while the other initiates the assembly of the nascent replication product into a viral ribonucleoprotein complex. Structural and biochemical studies of influenza virus RNA polymerase in complex with host acidic nuclear phosphoprotein 32 (ANP32) show how ANP32-mediated polymerase dimerization enables the replication of influenza viral RNA in a host-dependent manner.

DOI: 10.1038/s41586-020-2927-z

Source: https://www.nature.com/articles/s41586-020-2927-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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