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.
Highlights
In order to establish productive infection and dissemination, viruses usually evolve a number of strategies to hijack and/or subvert the host defense systems
Bub1-deficient flies are more resistant to Drosophila C virus (DCV) infection
To identify potential host factors participating in antiviral responses, we developed a machine-learning algorithm using a support vector machine to score each Drosophila gene according to the likelihood of involvement in viral infection
Summary
In order to establish productive infection and dissemination, viruses usually evolve a number of strategies to hijack and/or subvert the host defense systems. IMPORTANCE In this work, we identify for the first time that the nuclear protein Bub (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. Our data implicate a previously unknown function of Bub that can be hijacked by pathogens to facilitate their entry, and Bub may serve as a potential antiviral therapy target for limiting viral entry. The RNAi mechanism provides a broad spectrum of antiviral activities in the blockage of viral genome transcription [13, 14], while the inducible JAK-STAT signaling pathway has been found to offer efficient defense against viruses of the Dicistroviridae family (e.g., Drosophila C virus [DCV] and Cricket paralysis virus [CrPV]) [8]. The autophagy pathway contributes to antiviral potency to limit Vesicular stomatitis virus (VSV) and Rift Valley fever virus (RVFV) infection in flies [9, 18, 19]
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