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A Novel Interaction Network Used by Potyviruses in Virus-Host Interactions at the Protein Level.

ABSTRACT: Host proteins that are central to infection of potyviruses (genus Potyvirus; family Potyviridae) include the eukaryotic translation initiation factors eIF4E and eIF(iso)4E. The potyviral genome-linked protein (VPg) and the helper component proteinase (HCpro) interact with each other and with eIF4E and eIF(iso)4E and proteins are involved in the same functions during viral infection. VPg interacts with eIF4E/eIF(iso)4E via the 7-methylguanosine cap-binding region, whereas HCpro interacts with eIF4E/eIF(iso)4E via the 4E-binding motif YXXXXL?, similar to the motif in eIF4G. In this study, HCpro and VPg were found to interact in the nucleus, nucleolus, and cytoplasm in cells infected with the potyvirus potato virus A (PVA). In the cytoplasm, interactions between HCpro and VPg occurred in punctate bodies not associated with viral replication vesicles. In addition to HCpro, the 4E-binding motif was recognized in VPg of PVA. Mutations in the 4E-binding motif of VPg from PVA weakened interactions with eIF4E and heavily reduced PVA virulence. Furthermore, mutations in the 4G-binding domain of eIF4E reduced interactions with VPg and abolished interactions with HCpro. Thus, HCpro and VPg can both interact with eIF4E using the 4E-binding motif. Our results suggest a novel interaction network used by potyviruses to interact with host plants via translation initiation factors.

SUBMITTER: Ala-Poikela M

PROVIDER: S-EPMC6950583 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A Novel Interaction Network Used by Potyviruses in Virus-Host Interactions at the Protein Level.

Ala-Poikela Marjo M Rajamäki Minna-Liisa ML Valkonen Jari P T JPT

Viruses 20191214 12

Host proteins that are central to infection of potyviruses (genus <i>Potyvirus</i>; family Potyviridae) include the eukaryotic translation initiation factors eIF4E and eIF(iso)4E. The potyviral genome-linked protein (VPg) and the helper component proteinase (HCpro) interact with each other and with eIF4E and eIF(iso)4E and proteins are involved in the same functions during viral infection. VPg interacts with eIF4E/eIF(iso)4E via the 7-methylguanosine cap-binding region, whereas HCpro interacts w ...[more]

PMID: 31847316

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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:Host-pathogen interactions are crucial for the successful propagation of pathogens inside the host cell. Knowledge of interactions between host proteins and viral proteins or viral RNA may provide clues for developing novel antiviral strategies. Hepatitis E virus (HEV), a water-borne pathogen that causes acute hepatitis in humans, is responsible for epidemics in developing countries. HEV pathology and molecular biology have been poorly explored due to the lack of efficient culture systems. A contemporary approach, to better understand the viral infection cycle at the molecular level, is the use of system biology tools depicting virus-host interactions. To determine the host proteins which participate in the regulation of HEV replication, we indentified liver cell proteins interacting with HEV RNA at its putative promoter region and those interacting with HEV polymerase (RdRp) protein. We employed affinity chromatography followed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) to identify the interacting host proteins. Protein-protein interaction networks (PPI) were plotted and analyzed using web-based tools. Topological analysis of the network revealed that the constructed network is potentially significant and relevant for viral replication. Gene ontology and pathway enrichment analysis revealed that HEV RNA promoter- and polymerase-interacting host proteins belong to different cellular pathways such as RNA splicing, RNA metabolism, protein processing in endoplasmic reticulum, unfolded protein response, innate immune pathways, secretory vesicle pathway, and glucose metabolism. We showed that hnRNPK and hnRNPA2B1 interact with both HEV putative promoters and HEV RdRp, which suggest that they may have crucial roles in HEV replication. We demonstrated in vitro binding of hnRNPK and hnRNPA2B1 proteins with the HEV targets in the study, assuring the authenticity of the interactions obtained through mass spectrometry. Thus, our study highlights the ability of viruses, such as HEV, to maneuver host systems to create favorable cellular environments for virus propagation. Studying the host-virus interactions can facilitate the identification of antiviral therapeutic strategies and novel targets.

Project description:To study virus-host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions-viral-viral or host-host interactions-are constantly targeted and inhibited by exogenous interfaces mediating viral-host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these "hub proteins" evolve. "Party hubs" have multiple interfaces; they establish simultaneous/stable (domain-domain) interactions, and tend to evolve slowly. On the other hand, "date hubs" have few interfaces; they establish transient/weak (domain-motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein-protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus-host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus-host protein interactions.

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A Novel Interaction Network Used by Potyviruses in Virus-Host Interactions at the Protein Level.

Publications

A Novel Interaction Network Used by Potyviruses in Virus-Host Interactions at the Protein Level.

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