The dynein light chain 8 binding motif of rabies virus phosphoprotein promotes efficient viral transcription
The dynein light chain 8 binding motif of rabies virus phosphoprotein promotes efficient viral transcription
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DOI：
10.1073/pnas.0701397104
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发表时间：
2007-04
期刊：
影响因子：
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通讯作者：
G. Tan;Mirjam A. R. Preuss;John C. Williams;M. Schnell
中科院分区：
文献类型：
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作者：
G. Tan;Mirjam A. R. Preuss;John C. Williams;M. Schnell
近年来的研究表明，狂犬病病毒（RV）磷蛋白与动力蛋白轻链8（LC 8）之间的相互作用是RV致病的关键。通过与动力蛋白马达复合物的结合，LC 8被认为是将病毒核糖核蛋白连接到宿主细胞转运系统的分子因子。然而，最近的结构研究对这一模型提出了质疑。为了了解LC 8在RV发病机制中的作用，我们产生了具有或不具有从RV磷蛋白缺失的LC 8结合结构域（LC 8-BD）的重组RV。成年小鼠的外周感染表明，除去LC 8-BD并不抑制进入CNS，尽管它阻止了RV诱导的CNS疾病的发作。然而，LC 8-BD的缺失显著减弱了CNS中的病毒转录和复制。在感染相同重组RV的RAG 2敲除（KO）小鼠中的研究证实了这一发现，并表明适应性免疫系统不是感染早期病毒复制减弱的因素。在细胞培养中，LC 8-BD的缺失大大减弱了神经元细胞的生长，而非神经元细胞的生长模式保持不变。然而，LC 8-BD的缺失不影响RV病毒体的产生。我们提供的证据表明，去除LC 8-BD降低初级转录。在这项研究中，我们提出，LC 8不发挥作用的RV的逆行轴突运输和LC 8-BD的缺失损害病毒粒子的感染性，通过减少早期的转录和复制在神经元中。
Recent studies indicate that the interaction between rabies virus (RV) phosphoprotein and the dynein light chain 8 (LC8) is essential for RV pathogenesis. Through its association with the dynein motor complex, LC8 has been suggested as a molecular factor that links the viral ribonucleoprotein to the host cell transport system. Recent structural investigations, however, dispute this model. To understand the role of LC8 in RV pathogenesis, we generated recombinant RVs with or without the LC8 binding domain (LC8-BD) deleted from the RV phosphoprotein. Peripheral infection of adult mice showed that removal of the LC8-BD did not inhibit entry into the CNS, although it prevented onset of RV-induced CNS disease. However, deletion of the LC8-BD significantly attenuated viral transcription and replication in the CNS. Studies in RAG2 knockout (KO) mice infected with the same recombinant RVs confirmed this finding and indicated that the adaptive immune system is not a factor in the attenuation of viral replication early in the infection. In cell culture, the deletion of the LC8-BD greatly attenuated growth on neuronal cells whereas the growth pattern on nonneuronal cells remained unchanged. However, deletion of the LC8-BD did not affect production of RV virions. We provide evidence that removal of the LC8-BD decreases primary transcription. In this study, we propose that LC8 does not play a role in the retrograde axonal transport of RV and that the deletion of the LC8-BD impairs the infectivity of the virions by reducing early transcription and replication in neurons.