Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1006778
Title: Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
Authors: Too I.H.K. 
Bonne I. 
Tan E.L. 
Chu J.J.H. 
Alonso S. 
Keywords: alpha enolase
antineoplastic agent
asudemotide
immunoglobulin G
mitogen activated protein kinase
peripherin
phosphatidylethanolamine binding protein
prohibitin
protein disulfide isomerase
rocaglamide
small interfering RNA
stomatin
unclassified drug
virus capsid antigen
antivirus agent
benzofuran derivative
nerve protein
prohibitin
repressor protein
animal cell
animal experiment
animal model
Article
bioinformatics
cell proliferation
cell viability assay
chikungunya
controlled study
cytotoxicity
dengue
Enterovirus A71
Enterovirus infection
flow cytometry
gene silencing
genetic transfection
hepatitis C
host pathogen interaction
human
human cell
immunofluorescence
immunohistochemistry
immunoprecipitation
luciferase assay
mass spectrometry
mitochondrial membrane potential
molecular genetics
mouse
neuroblastoma
neuropathology
nonhuman
proteomics
rhabdomyosarcoma
signal transduction
transmission electron microscopy
viral plaque assay
Western blotting
animal
antagonists and inhibitors
cell line
cell membrane
drug effect
Enterovirus A
Enterovirus infection
genetics
germfree animal
host pathogen interaction
knockout mouse
metabolism
mitochondrial membrane
nerve cell
pathogenicity
pathology
physiology
procedures
RNA interference
survival analysis
ultrastructure
virology
virus entry
virus replication
Animals
Antiviral Agents
Benzofurans
Cell Line
Cell Membrane
Enterovirus A, Human
Enterovirus Infections
Host-Pathogen Interactions
Humans
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Mitochondrial Membranes
Nerve Tissue Proteins
Neurons
Proteomics
Repressor Proteins
RNA Interference
Specific Pathogen-Free Organisms
Survival Analysis
Virus Internalization
Virus Replication
Issue Date: 2018
Publisher: Public Library of Science
Citation: Too I.H.K., Bonne I., Tan E.L., Chu J.J.H., Alonso S. (2018). Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis. PLoS Pathogens 14 (1) : e1006778. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1006778
Abstract: A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications. © 2018 Too et al.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/165623
ISSN: 15537366
DOI: 10.1371/journal.ppat.1006778
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