Bub1 Facilitates Virus Entry through Endocytosis in a Model of Drosophila Pathogenesis.
Bub1 Facilitates Virus Entry through Endocytosis in a Model of Drosophila Pathogenesis.
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Bub1 在果蝇发病机制模型中通过内吞作用促进病毒进入
DOI：
10.1128/jvi.00254-18
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发表时间：
2018-09-15
影响因子：
5.4
通讯作者：
Pan L
中科院分区：
文献类型：
--
作者：
Yang S;Yu J;Fan Z;Gong ST;Tang H;Pan L
在这项工作中，我们确定的第一次，核蛋白Bub1（出芽不受抑制的苯并咪唑1），一个高度保守的亚基的动粒复合体调节染色体congression，有一个新的和重要的功能，在细胞膜上，以促进病毒进入宿主细胞。Bub1缺陷使宿主具有抵抗果蝇和人类细胞系中病毒感染的能力。Bub1通过调节内吞作用参与病毒进入步骤。DCV衣壳蛋白可以募集Bub1，并且DCV感染可以加强Bub1与网格蛋白依赖性内吞组分之间的相互作用。水泡性口炎病毒（VSV）和单核细胞增生李斯特菌在bub1缺陷苍蝇和细胞系的限制进入。因此，我们的数据暗示了Bub1以前未知的功能，可以被病原体劫持以促进其进入，Bub1可能作为限制病毒进入的潜在抗病毒治疗靶点。为了建立生产性感染和传播，病毒通常会进化出许多策略来劫持和/或破坏宿主的防御系统。然而，病毒利用宿主因子来促进感染的特征仍然很差。在这项工作中，我们发现，不受苯并咪唑1（bub1）（一种调节染色体聚集的动粒复合体的高度保守亚基）抑制的出芽缺陷的黑腹果蝇（Drosophila melanogaster）变得对果蝇C病毒（DCV）感染具有抗性，与野生型对照相比，存活率增加，病毒载量减少。机制分析进一步表明，Bub1也在细胞质中发挥作用，主要参与DCV和其他病原体的网格蛋白依赖性内吞作用，从而限制病原体进入。DCV感染可能增强了Bub1与细胞膜上网格蛋白接头的相互作用。此外，在哺乳动物细胞系中也验证了Bub1的保守功能。因此，我们的数据证明了Bub1以前未知的功能，可以被病原体劫持，以促进它们的感染和传播。重要性在这项工作中，我们首次发现，核蛋白Bub 1（出芽不受苯并咪唑1抑制），一个高度保守的亚基的动粒复合体调节染色体congression，有一个新的和重要的功能，在细胞膜上，以促进病毒进入宿主细胞。Bub1缺陷使宿主具有抵抗果蝇和人类细胞系中病毒感染的能力。Bub1通过调节内吞作用参与病毒进入步骤。DCV衣壳蛋白可以募集Bub1，并且DCV感染可以加强Bub1与网格蛋白依赖性内吞组分之间的相互作用。水泡性口炎病毒（VSV）和单核细胞增生李斯特菌在bub1缺陷苍蝇和细胞系的限制进入。因此，我们的数据暗示了Bub1以前未知的功能，可以被病原体劫持以促进其进入，Bub1可能作为限制病毒进入的潜在抗病毒治疗靶点。
In this work, we identify for the first time that the nuclear protein Bub1 (budding uninhibited by benzimidazoles 1), a highly conserved subunit of the kinetochore complex regulating chromosome congression, has a novel and important function on the cell membrane to facilitate the virus to enter host cells. Bub1 deficiency empowers the host to have the ability to resist viral infection in Drosophila and a human cell line. Bub1 is involved in the virus entry step through regulating endocytosis. The DCV capsid protein can recruit Bub1, and DCV infection can strengthen the interaction between Bub1 and a clathrin-dependent endocytosis component. The restricted entry of vesicular stomatitis virus (VSV) and Listeria monocytogenes in bub1-deficient flies and cell lines was also observed. Therefore, our data implicate a previously unknown function of Bub1 that can be hijacked by pathogens to facilitate their entry, and Bub1 may serve as a potential antiviral therapy target for limiting viral entry. ABSTRACT In order to establish productive infection and dissemination, viruses usually evolve a number of strategies to hijack and/or subvert the host defense systems. However, host factors utilized by the virus to facilitate infection remain poorly characterized. In this work, we found that Drosophila melanogaster deficient in budding uninhibited by benzimidazoles 1 (bub1), a highly conserved subunit of the kinetochore complex regulating chromosome congression (1), became resistant to Drosophila C virus (DCV) infection, evidenced in increased survival rates and reduced viral loads, compared to the wild-type control. Mechanistic analysis further showed that Bub1 also functioned in the cytoplasm and was essentially involved in clathrin-dependent endocytosis of DCV and other pathogens, thus limiting pathogen entry. DCV infection potentially had strengthened the interaction between Bub1 and the clathrin adaptor on the cell membrane. Furthermore, the conserved function of Bub1 was also verified in a mammalian cell line. Thus, our data demonstrated a previously unknown function of Bub1 that could be hijacked by pathogens to facilitate their infection and spread. IMPORTANCE In this work, we identify for the first time that the nuclear protein Bub1 (budding uninhibited by benzimidazoles 1), a highly conserved subunit of the kinetochore complex regulating chromosome congression, has a novel and important function on the cell membrane to facilitate the virus to enter host cells. Bub1 deficiency empowers the host to have the ability to resist viral infection in Drosophila and a human cell line. Bub1 is involved in the virus entry step through regulating endocytosis. The DCV capsid protein can recruit Bub1, and DCV infection can strengthen the interaction between Bub1 and a clathrin-dependent endocytosis component. The restricted entry of vesicular stomatitis virus (VSV) and Listeria monocytogenes in bub1-deficient flies and cell lines was also observed. Therefore, our data implicate a previously unknown function of Bub1 that can be hijacked by pathogens to facilitate their entry, and Bub1 may serve as a potential antiviral therapy target for limiting viral entry.