An Influenza A virus can evolve to use human ANP32E through altering polymerase dimerization.
An Influenza A virus can evolve to use human ANP32E through altering polymerase dimerization.
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DOI：
10.1038/s41467-023-41308-4
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发表时间：
2023-10-10
影响因子：
16.6
通讯作者：
Barclay, Wendy S.
中科院分区：
文献类型：
--
作者：
Sheppard, Carol M.;Goldhill, Daniel H.;Swann, Olivia C.;Staller, Ecco;Penn, Rebecca;Platt, Olivia K.;Sukhova, Ksenia;Baillon, Laury;Frise, Rebecca;Peacock, Thomas P.;Fodor, Ervin;Barclay, Wendy S.
人ANP32A和ANP32B是流感病毒基因组复制的必需但冗余的宿主因子。虽然大多数流感病毒不能在缺乏ANP32A和ANP32B的编辑的人类细胞中复制，但一些毒株表现出有限的生长。在这里，我们在这些编辑的细胞中实验性地进化出这样的甲型流感病毒，并且出乎意料地，在2次传代后，我们观察到稳健的病毒生长。我们在流感聚合酶的不同亚基中发现了两个突变，这使得突变病毒能够使用一种新的宿主因子ANP 32 E，这是一种替代的家族成员，它无法支持野生型聚合酶。两种突变都存在于两种聚合酶复合物之间的对称二聚体界面中并减少聚合酶二聚化。这些突变先前已被确定为使流感病毒适应小鼠。事实上，进化的病毒获得了使用次优小鼠ANP 32蛋白的能力，并在小鼠中变得更具毒性。我们确定了对称二聚体界面中的进一步突变，我们预测这些突变允许流感通过类似的机制适应使用次优的ANP32蛋白。总体而言，我们的研究结果表明流感病毒聚合酶的不对称和对称二聚体之间的平衡，这是由聚合酶和ANP 32宿主蛋白之间的相互作用的影响。尽管人类ANP32A和ANP32B是流感病毒基因组复制的冗余宿主因子。在这项工作中，作者表明，在缺乏ANP32A和ANP32B的细胞中生长的流感病毒进化为使用ANP32E。他们探索了能够实现这一点的聚合酶突变，并证明了小鼠的毒性增加。
Human ANP32A and ANP32B are essential but redundant host factors for influenza virus genome replication. While most influenza viruses cannot replicate in edited human cells lacking both ANP32A and ANP32B, some strains exhibit limited growth. Here, we experimentally evolve such an influenza A virus in these edited cells and unexpectedly, after 2 passages, we observe robust viral growth. We find two mutations in different subunits of the influenza polymerase that enable the mutant virus to use a novel host factor, ANP32E, an alternative family member, which is unable to support the wild type polymerase. Both mutations reside in the symmetric dimer interface between two polymerase complexes and reduce polymerase dimerization. These mutations have previously been identified as adapting influenza viruses to mice. Indeed, the evolved virus gains the ability to use suboptimal mouse ANP32 proteins and becomes more virulent in mice. We identify further mutations in the symmetric dimer interface which we predict allow influenza to adapt to use suboptimal ANP32 proteins through a similar mechanism. Overall, our results suggest a balance between asymmetric and symmetric dimers of influenza virus polymerase that is influenced by the interaction between polymerase and ANP32 host proteins. Despite their essentiality, human ANP32A and ANP32B are redundant host factors for influenza virus genome replication. In this work, authors show that an influenza virus grown in cells lacking ANP32A and ANP32B evolved to use ANP32E. They explore the polymerase mutations that enable this, and demonstrate increased virulence in mice.
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