Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection
Nucleozin Targets Cytoplasmic Trafficking of Viral Ribonucleoprotein-Rab11 Complexes in Influenza A Virus Infection
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DOI：
10.1128/jvi.03123-12
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发表时间：
2013-04-01
影响因子：
5.4
通讯作者：
Digard, Paul
中科院分区：
文献类型：
--
作者：
Amorim, Maria Joao;Kao, Richard Y.;Digard, Paul
需要新的抗病毒药物来补充现有的甲型流感病毒控制策略。最近发现了以病毒核蛋白(NP)为靶点的一种有希望的新药，以复合核苷为例。这些抑制剂被认为是稳定NP单体之间相互作用的“分子钉”，促进无功能聚集体的形成。在这里，我们详细介绍了核苷的抑制机制，发现该药物对IAV的生命周期既有早期作用，也有晚期作用。如果在感染开始时存在，它会抑制病毒RNA和蛋白质的合成。然而，当在以后的时间点加入时，它仍然有效地阻止了感染性后代的产生，但不影响病毒大分子的合成。相反，核苷阻止了经历核出口的核糖核蛋白(RNPs)的细胞质运输，促进了RNPs与细胞Rab11一起形成大的核周聚集体。这种效应导致病毒颗粒的数量大大减少，通常明显更小。我们的结论是，核苷的主要靶点是病毒的RNP，而不是NP，这项工作也证明了通过阻断病毒基因组的细胞质运输可以有效地抑制IAV复制的原理。
Novel antivirals are needed to supplement existing control strategies for influenza A virus (IAV). A promising new class of drug, exemplified by the compound nucleozin, has recently been identified that targets the viral nucleoprotein (NP). These inhibitors are thought to act as "molecular staples" that stabilize interactions between NP monomers, promoting the formation of nonfunctional aggregates. Here we detail the inhibitory mechanism of nucleozin, finding that the drug has both early-and late-acting effects on the IAV life cycle. When present at the start of infection, it inhibited viral RNA and protein synthesis. However, when added at later time points, it still potently blocked the production of infectious progeny but without affecting viral macromolecular synthesis. Instead, nucleozin blocked the cytoplasmic trafficking of ribonucleoproteins (RNPs) that had undergone nuclear export, promoting the formation of large perinuclear aggregates of RNPs along with cellular Rab11. This effect led to the production of much reduced amounts of often markedly smaller virus particles. We conclude that the primary target of nucleozin is the viral RNP, not NP, and this work also provides proof of the principle that IAV replication can be effectively inhibited by blocking cytoplasmic trafficking of the viral genome.