Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication.
Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication.
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DOI：
10.1371/journal.ppat.1003744
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发表时间：
2013-10
期刊：
影响因子：
6.7
通讯作者：
Wozniak RW
中科院分区：
文献类型：
--
作者：
Neufeldt CJ;Joyce MA;Levin A;Steenbergen RH;Pang D;Shields J;Tyrrell DL;Wozniak RW
丙型肝炎病毒（HCV）感染诱导宿主细胞质中膜状网状结构的形成，其中病毒基因组复制和病毒粒子组装。人们认为膜状网可以浓缩病毒成分并将病毒RNA隐藏起来，使其免受模式识别受体的影响。我们已经发现了核孔复合物蛋白（NUPS）和核转运因子（NTFs）在膜网中的作用。我们发现，HCV感染导致细胞质Nups的水平增加，这些Nups积累在富含HCV蛋白的位点。此外，我们检测到特定的HCV蛋白质之间的相互作用和NUPS和NTFs。我们推测位于细胞质中的Nups促进了膜网的形成，并有助于病毒复制的区室化。因此，我们表明，通常针对细胞核的转运货物蛋白能够进入膜网的区域，并且特定Nups或Kaps的耗尽抑制HCV复制和组装。丙型肝炎病毒（HCV）是一种正链RNA病毒，是全球肝病的主要原因，影响超过1.7亿人。细胞感染丙型肝炎病毒会导致宿主细胞胞质膜重排为病毒复制和组装复合物，统称为膜网。这种膜状网被认为参与了病毒成分的浓缩和免疫逃避，尽管实现这些功能的机制仍然是该领域的一个重要问题。在这里，我们报告说，核膜结构，运输大分子进出细胞核，称为核孔复合物（NPC），也存在于感染HCV和其他正链RNA病毒的细胞膜网。我们的研究结果表明，这些NPC的功能，以调节进入膜网内部的蛋白质的访问，从而有助于建立一个有利于病毒复制和病毒免疫逃避的环境。与这一想法相一致，我们表明，NPC蛋白所需的HCV组装。我们发现核转运蛋白在HCV复制中起作用，并且可能在其他病毒感染中起作用，这可能导致发现抗病毒治疗的新靶点。
Hepatitis C virus (HCV) infection induces formation of a membranous web structure in the host cell cytoplasm where the viral genome replicates and virions assemble. The membranous web is thought to concentrate viral components and hide viral RNA from pattern recognition receptors. We have uncovered a role for nuclear pore complex proteins (Nups) and nuclear transport factors (NTFs) in the membranous web. We show that HCV infection leads to increased levels of cytoplasmic Nups that accumulate at sites enriched for HCV proteins. Moreover, we detected interactions between specific HCV proteins and both Nups and NTFs. We hypothesize that cytoplasmically positioned Nups facilitate formation of the membranous web and contribute to the compartmentalization of viral replication. Accordingly, we show that transport cargo proteins normally targeted to the nucleus are capable of entering regions of the membranous web, and that depletion of specific Nups or Kaps inhibits HCV replication and assembly. Hepatitis C virus (HCV) is a positive strand RNA virus and is a major cause of liver disease worldwide, affecting more than 170 million individuals. Infection of cells with HCV leads to rearrangement of cytoplasmic host cell membranes into viral replication and assembly complexes collectively known as the membranous web. This membranous web is thought to be involved in concentrating viral components and immune evasion, though the mechanisms by which these functions are achieved remains an important question in the field. Here, we report that nuclear envelope structures that transport macromolecules into and out of the nucleus, termed nuclear pore complexes (NPCs), are also present in the membranous web of cells infected with HCV and other positive strand RNA viruses. Our results suggest that these NPCs function to regulate access of proteins into the interior of the membranous web, thus contributing to the establishment of an environment conducive to viral replication and viral immune evasion. Consistent with this idea, we show that NPC proteins are required for HCV assembly. Our discovery that nuclear transport proteins play a role in HCV replication, and potentially other viral infections, may lead to the discovery of new targets for antiviral therapies.
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