Elucidation of the Ebola Virus VP24 Cellular Interactome and Disruption of Virus Biology through Targeted Inhibition of Host-Cell Protein Function
Elucidation of the Ebola Virus VP24 Cellular Interactome and Disruption of Virus Biology through Targeted Inhibition of Host-Cell Protein Function
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DOI：
10.1021/pr500556d
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发表时间：
2014-11-01
影响因子：
4.4
通讯作者：
Hiscox, Julian A.
中科院分区：
文献类型：
--
作者：
Garcia-Dorival, Isabel;Wu, Weining;Hiscox, Julian A.
病毒在感染细胞中的发病机制是抗病毒反应和宿主细胞过程破坏之间的平衡。许多病毒蛋白特异性地与宿主细胞蛋白相互作用以促进病毒生物学。了解这些相互作用可以获得有关感染的知识，并为抗病毒治疗提供潜在的靶点。其中一种病毒是埃博拉病毒，它对人类健康产生了深远的影响，并导致病毒性出血热，病死率可接近90%。埃博拉病毒VP24蛋白在逃避宿主免疫反应中起着关键作用，并且可能与多种细胞蛋白相互作用。为了绘制这些相互作用并更好地理解VP24的潜在功能，使用无标记定量蛋白质组学来鉴定具有形成VP24细胞相互作用组的高概率的细胞蛋白质。几种已知的相互作用得到了证实，因此对该技术充满信心，但也发现了新的相互作用，包括与ATP 1A1的相互作用，ATP 1A1参与了细胞调节和细胞信号传导。用小分子抑制剂破坏埃博拉病毒感染细胞中ATP 1A1的活性导致子代病毒减少，从而说明了定量蛋白质组学如何用于识别潜在的治疗靶点。
Viral pathogenesis in the infected cell is a balance between antiviral responses and subversion of host-cell processes. Many viral proteins specifically interact with host-cell proteins to promote virus biology. Understanding these interactions can lead to knowledge gains about infection and provide potential targets for antiviral therapy. One such virus is Ebola, which has profound consequences for human health and causes viral hemorrhagic fever where case fatality rates can approach 90%. The Ebola virus VP24 protein plays a critical role in the evasion of the host immune response and is likely to interact with multiple cellular proteins. To map these interactions and better understand the potential functions of VP24, label-free quantitative proteomics was used to identify cellular proteins that had a high probability of forming the VP24 cellular interactome. Several known interactions were confirmed, thus placing confidence in the technique, but new interactions were also discovered including one with ATP1A1, which is involved in osmoregulation and cell signaling. Disrupting the activity of ATP1A1 in Ebola-virus-infected cells with a small molecule inhibitor resulted in a decrease in progeny virus, thus illustrating how quantitative proteomics can be used to identify potential therapeutic targets.