Cargando…

Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with hepara...

Descripción completa

Detalles Bibliográficos
Autores principales: Lefèvre, Mathieu, Felmlee, Daniel J., Parnot, Marie, Baumert, Thomas F., Schuster, Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994096/
https://www.ncbi.nlm.nih.gov/pubmed/24751902
http://dx.doi.org/10.1371/journal.pone.0095550
_version_ 1782312668182347776
author Lefèvre, Mathieu
Felmlee, Daniel J.
Parnot, Marie
Baumert, Thomas F.
Schuster, Catherine
author_facet Lefèvre, Mathieu
Felmlee, Daniel J.
Parnot, Marie
Baumert, Thomas F.
Schuster, Catherine
author_sort Lefèvre, Mathieu
collection PubMed
description Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE’s HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection.
format Online
Article
Text
id pubmed-3994096
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39940962014-04-25 Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E Lefèvre, Mathieu Felmlee, Daniel J. Parnot, Marie Baumert, Thomas F. Schuster, Catherine PLoS One Research Article Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE’s HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection. Public Library of Science 2014-04-21 /pmc/articles/PMC3994096/ /pubmed/24751902 http://dx.doi.org/10.1371/journal.pone.0095550 Text en © 2014 Lefèvre et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lefèvre, Mathieu
Felmlee, Daniel J.
Parnot, Marie
Baumert, Thomas F.
Schuster, Catherine
Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title_full Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title_fullStr Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title_full_unstemmed Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title_short Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E
title_sort syndecan 4 is involved in mediating hcv entry through interaction with lipoviral particle-associated apolipoprotein e
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994096/
https://www.ncbi.nlm.nih.gov/pubmed/24751902
http://dx.doi.org/10.1371/journal.pone.0095550
work_keys_str_mv AT lefevremathieu syndecan4isinvolvedinmediatinghcventrythroughinteractionwithlipoviralparticleassociatedapolipoproteine
AT felmleedanielj syndecan4isinvolvedinmediatinghcventrythroughinteractionwithlipoviralparticleassociatedapolipoproteine
AT parnotmarie syndecan4isinvolvedinmediatinghcventrythroughinteractionwithlipoviralparticleassociatedapolipoproteine
AT baumertthomasf syndecan4isinvolvedinmediatinghcventrythroughinteractionwithlipoviralparticleassociatedapolipoproteine
AT schustercatherine syndecan4isinvolvedinmediatinghcventrythroughinteractionwithlipoviralparticleassociatedapolipoproteine