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Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

ABSTRACT: Hepatitis E virus (HEV) is endemic worldwide and a major cause of acute liver disease in developing countries. However, the molecular mechanisms of liver pathology and clinical disease are not well understood for HEV infection. Open reading frame 3 (ORF3) of HEV encodes a small phosphoprotein, which is assumed to be involved in liver pathology and clinical disease. In this study, the interactions between the HEV ORF3 protein and human proteins were investigated using a stringent, high-throughput yeast two-hybrid (Y2H) analysis. Thirty two proteins were shown to interact with genotype 1 ORF3, 28 of which have not been reported previously. These novel interactions were evaluated by coimmunoprecipitation of protein complexes from transfected cells. We found also that the ORF3 proteins of genotype 4 and rabbit HEV interacted with all of the human proteins identified by the genotype 1 ORF3 protein. However, the putative ORF3 protein derived from avian HEV did not interact with the majority of these human proteins. The identified proteins were used to infer an overall interaction map linking the ORF3 protein with components of the host cellular networks. Analysis of this interaction map, based on functional annotation with the Gene Ontology features and KEGG pathways, revealed an enrichment of host proteins involved in complement coagulation, cellular iron ion homeostasis and oxidative stress. Additional canonical pathway analysis highlighted the enriched biological pathways relevant to blood coagulation and hemostasis. Consideration of the clinical manifestations of hepatitis E reported previously and the results of biological analysis from this study suggests that the ORF3 protein is likely to lead to an imbalance of coagulation and fibrinolysis by interacting with host proteins and triggering the corresponding pathological processes. These results suggest critical approaches to further study of the pathogenesis of the HEV ORF3 protein.

SUBMITTER: Geng Y

PROVIDER: S-EPMC3571956 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

Geng Yansheng Y Yang Jun J Huang Weijin W Harrison Tim J TJ Zhou Yan Y Wen Zhiheng Z Wang Youchun Y

PloS one 20130213 2

Hepatitis E virus (HEV) is endemic worldwide and a major cause of acute liver disease in developing countries. However, the molecular mechanisms of liver pathology and clinical disease are not well understood for HEV infection. Open reading frame 3 (ORF3) of HEV encodes a small phosphoprotein, which is assumed to be involved in liver pathology and clinical disease. In this study, the interactions between the HEV ORF3 protein and human proteins were investigated using a stringent, high-throughput ...[more]

PMID: 23418552

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Project description:BackgroundInfectious diseases are a cruel assassin with millions of victims around the world each year. Understanding infectious mechanism of viruses is indispensable for their inhibition. One of the best ways of unveiling this mechanism is to investigate the host-pathogen protein-protein interaction network. In this paper we try to disclose many properties of this network. We focus on human as host and integrate experimentally 32,859 interaction between human proteins and virus proteins from several databases. We investigate different properties of human proteins targeted by virus proteins and find that most of them have a considerable high centrality scores in human intra protein-protein interaction network. Investigating human proteins network properties which are targeted by different virus proteins can help us to design multipurpose drugs.ResultsAs host-pathogen protein-protein interaction network is a bipartite network and centrality measures for this type of networks are scarce, we proposed seven new centrality measures for analyzing bipartite networks. Applying them to different virus strains reveals unrandomness of attack strategies of virus proteins which could help us in drug design hence elevating the quality of life. They could also be used in detecting host essential proteins. Essential proteins are those whose functions are critical for survival of its host. One of the proposed centralities named diversity of predators, outperforms the other existing centralities in terms of detecting essential proteins and could be used as an optimal essential proteins' marker.ConclusionsDifferent centralities were applied to analyze human protein-protein interaction network and to detect characteristics of human proteins targeted by virus proteins. Moreover, seven new centralities were proposed to analyze host-pathogen protein-protein interaction network and to detect pathogens' favorite host protein victims. Comparing different centralities in detecting essential proteins reveals that diversity of predator (one of the proposed centralities) is the best essential protein marker.

Project description:Viruses reshape the intracellular environment of their hosts, largely through protein-protein interactions, to co-opt processes necessary for viral infection and interference with antiviral defences. Due to genome size constraints and the concomitant limited coding capacity of viruses, viral proteins are generally multifunctional and have evolved to target diverse host proteins. Inference of the virus-host interaction network can be instrumental for understanding how viruses manipulate the host machinery and how re-wiring of specific pathways can contribute to disease. Here, we use affinity purification and mass spectrometry analysis (AP-MS) to define the global landscape of interactions between the geminivirus Tomato yellow leaf curl virus (TYLCV) and its host Nicotiana benthamiana. For this purpose, we expressed tagged versions of each of TYLCV-encoded proteins (C1/Rep, C2/TrAP, C3/REn, C4, V2, and CP) in planta in the presence of the virus. Using a quantitative scoring system, 728 high-confidence plant interactors were identified, and the interaction network of each viral protein was inferred; TYLCV-targeted proteins are more connected than average, and connect with other proteins through shorter paths, which would allow the virus to exert large effects with few interactions. Comparative analyses of divergence patterns between N. benthamiana and potato, a non-host Solanaceae, showed evolutionary constraints on TYLCV-targeted proteins. Our results provide a comprehensive overview of plant proteins targeted by TYLCV during the viral infection, which may contribute to uncovering the underlying molecular mechanisms of plant viral diseases and provide novel potential targets for anti-viral strategies and crop engineering. Interestingly, some of the TYLCV-interacting proteins appear to be convergently targeted by other pathogen effectors, which suggests a central role for these proteins in plant-pathogen interactions, and pinpoints them as potential targets to engineer broad-spectrum resistance to biotic stresses.

Dataset Information

Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

Publications

Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

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