Yang Shiping, Fu Chen, Lian Xianyi, Dong Xiaobao, Zhang Ziding
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
mSystems. 2019 Apr 9;4(2). doi: 10.1128/mSystems.00303-18. eCollection 2019 Mar-Apr.
Computational analysis of human-virus protein-protein interaction (PPI) data is an effective way toward systems understanding the molecular mechanism of viral infection. Previous work has mainly focused on characterizing the global properties of viral targets within the entire human PPI network. In comparison, how viruses manipulate host local networks (e.g., human protein complexes) has been rarely addressed from a computational perspective. By mainly integrating information about human-virus PPIs, human protein complexes, and gene expression profiles, we performed a large-scale analysis of virally targeted complexes (VTCs) related to five common human-pathogenic viruses, including influenza A virus subtype H1N1, human immunodeficiency virus type 1, Epstein-Barr virus, human papillomavirus, and hepatitis C virus. We found that viral targets are enriched within human protein complexes. We observed in the context of VTCs that viral targets tended to have a high within-complex degree and to be scaffold and housekeeping proteins. Complexes that are essential for viral propagation were simultaneously targeted by multiple viruses. We characterized the periodic expression patterns of VTCs and provided the corresponding candidates that may be involved in the manipulation of the host cell cycle. As a potential application of the current analysis, we proposed a VTC-based antiviral drug target discovery strategy. Finally, we developed an online VTC-related platform known as VTcomplex (http://zzdlab.com/vtcomplex/index.php or http://systbio.cau.edu.cn/vtcomplex/index.php). We hope that the current analysis can provide new insights into the global landscape of human-virus PPIs at the VTC level and that the developed VTcomplex will become a vital resource for the community. Although human protein complexes have been reported to be directly related to viral infection, previous studies have not systematically investigated human-virus PPIs from the perspective of human protein complexes. To the best of our knowledge, we have presented here the most comprehensive and in-depth analysis of human-virus PPIs in the context of VTCs. Our findings confirm that human protein complexes are heavily involved in viral infection. The observed preferences of virally targeted subunits within complexes reflect the mechanisms used by viruses to manipulate host protein complexes. The identified periodic expression patterns of the VTCs and the corresponding candidates could increase our understanding of how viruses manipulate the host cell cycle. Finally, our proposed conceptual application framework of VTCs and the developed VTcomplex could provide new hints to develop antiviral drugs for the clinical treatment of viral infections.
对人类-病毒蛋白质-蛋白质相互作用（PPI）数据进行计算分析是系统理解病毒感染分子机制的有效途径。以往的工作主要集中在刻画整个人类PPI网络中病毒靶点的全局特性。相比之下，从计算角度很少探讨病毒如何操纵宿主局部网络（如人类蛋白质复合物）。通过主要整合关于人类-病毒PPI、人类蛋白质复合物和基因表达谱的信息，我们对与五种常见人类致病病毒相关的病毒靶向复合物（VTC）进行了大规模分析，这五种病毒包括甲型H1N1流感病毒、人类免疫缺陷病毒1型、爱泼斯坦-巴尔病毒、人乳头瘤病毒和丙型肝炎病毒。我们发现病毒靶点在人类蛋白质复合物中富集。在VTC的背景下，我们观察到病毒靶点往往在复合物内部具有较高的度数，并且是支架蛋白和管家蛋白。对病毒传播至关重要的复合物同时被多种病毒靶向。我们刻画了VTC的周期性表达模式，并提供了可能参与操纵宿主细胞周期的相应候选物。作为当前分析的一个潜在应用，我们提出了一种基于VTC的抗病毒药物靶点发现策略。最后，我们开发了一个名为VTcomplex的在线VTC相关平台（http://zzdlab.com/vtcomplex/index.php或http://systbio.cau.edu.cn/vtcomplex/index.php）。我们希望当前的分析能够在VTC层面为人类-病毒PPI的全局格局提供新的见解，并且开发的VTcomplex将成为该领域的重要资源。尽管已有报道称人类蛋白质复合物与病毒感染直接相关，但以往的研究尚未从人类蛋白质复合物的角度系统地研究人类-病毒PPI。据我们所知，我们在此展示了在VTC背景下对人类-病毒PPI最全面和深入的分析。我们的发现证实人类蛋白质复合物大量参与病毒感染。在复合物中观察到的病毒靶向亚基的偏好反映了病毒操纵宿主蛋白质复合物的机制。确定的VTC周期性表达模式和相应的候选物可以增进我们对病毒如何操纵宿主细胞周期的理解。最后，我们提出的VTC概念应用框架和开发的VTcomplex可以为开发用于病毒感染临床治疗的抗病毒药物提供新的线索。
