Dataset Information

Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.

ABSTRACT: Enterovirus A71 (EV-A71) is a major pathogen that causes severe and fatal cases of hand-foot-and-mouth disease (HFMD). HFMD caused by EV-A71 seriously endangers children's health. Although autophagy is an important antiviral defense mechanism, some viruses have evolved strategies to utilize autophagy to promote self-replication. EV-A71 can utilize autophagy vesicles as replication scaffolds, indicating that EV-A71 infection is closely related to its autophagy induction mechanism. VP1, a structural protein of EV-A71, has been reported to induce autophagy, but the underlying mechanism is still unclear. In this study, we found that the C-terminus (aa 251-297) of VP1 induces autophagy. Mass spectrometry analysis suggested that prohibitin 2 (PHB2) interacts with the C-terminus of the EV-A71 VP1 protein, and this was further verified by coimmunoprecipitation assays. After PHB2 knockdown, EV-A71 replication, viral particle release, and viral protein synthesis were reduced, and autophagy was inhibited. The results suggest that PHB2 interaction with VP1 is essential for induction of autophagy and the infectivity of EV-A71. Furthermore, we confirmed that EV-A71 induced complete autophagy that required autolysosomal acidification, thus affecting EV-A71 infection. In summary, this study revealed that the host protein PHB2 is involved in an autophagy mechanism during EV-A71 infection.

SUBMITTER: Su W

PROVIDER: S-EPMC7232526 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.

Su Weitao W Huang Shan S Zhu Huimin H Zhang Bao B Wu Xianbo X

Viruses 20200408 4

Enterovirus A71 (EV-A71) is a major pathogen that causes severe and fatal cases of hand-foot-and-mouth disease (HFMD). HFMD caused by EV-A71 seriously endangers children's health. Although autophagy is an important antiviral defense mechanism, some viruses have evolved strategies to utilize autophagy to promote self-replication. EV-A71 can utilize autophagy vesicles as replication scaffolds, indicating that EV-A71 infection is closely related to its autophagy induction mechanism. VP1, a structur ...[more]

PMID: 32276428

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Project description:BackgroundIn 2011-2012, Northern Vietnam experienced its first large scale hand foot and mouth disease (HFMD) epidemic. In 2011, a major HFMD epidemic was also reported in South Vietnam with fatal cases. This 2011-2012 outbreak was the first one to occur in North Vietnam providing grounds to study the etiology, origin and dynamic of the disease. We report here the analysis of the VP1 gene of strains isolated throughout North Vietnam during the 2011-2012 outbreak and before.MethodsThe VP1 gene of 106 EV-A71 isolates from North Vietnam and 2 from Central Vietnam were sequenced. Sequence alignments were analyzed at the nucleic acid and protein level. Gene polymorphism was also analyzed. A Factorial Correspondence Analysis was performed to correlate amino acid mutations with clinical parameters.ResultsThe sequences were distributed into four phylogenetic clusters. Three clusters corresponded to the subgenogroup C4 and the last one corresponded to the subgenogroup C5. Each cluster displayed different polymorphism characteristics. Proteins were highly conserved but three sites bearing only Isoleucine (I) or Valine (V) were characterized. The isoleucine/valine variability matched the clusters. Spatiotemporal analysis of the I/V variants showed that all variants which emerged in 2011 and then in 2012 were not the same but were all present in the region prior to the 2011-2012 outbreak. Some correlation was found between certain I/V variants and ethnicity and severity.ConclusionsThe 2011-2012 outbreak was not caused by an exogenous strain coming from South Vietnam or elsewhere but by strains already present and circulating at low level in North Vietnam. However, what triggered the outbreak remains unclear. A selective pressure is applied on I/V variants which matches the genetic clusters. I/V variants were shown on other viruses to correlate with pathogenicity. This should be investigated in EV-A71. I/V variants are an easy and efficient way to survey and identify circulating EV-A71 strains.

Project description:Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site.

Dataset Information

Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.

Publications

Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.

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