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https://hdl.handle.net/2440/62449
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Type: | Journal article |
Title: | The SR-BI partner PDZK1 facilitates Hepatitis C virus entry |
Author: | Eyre, N. Drummer, H. Beard, M. |
Citation: | PLoS Pathogens, 2010; 6(10):1-14 |
Publisher: | Public Library of Science |
Issue Date: | 2010 |
ISSN: | 1553-7366 1553-7374 |
Editor: | Rice, C.M. |
Statement of Responsibility: | Nicholas S. Eyre, Heidi E. Drummer and Michael R. Beard |
Abstract: | Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post-transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479–509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479–508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor. |
Keywords: | Cells, Cultured Hepatocytes Humans Hepacivirus Hepatitis C Carcinoma, Hepatocellular Liver Neoplasms Carrier Proteins Membrane Proteins RNA, Small Interfering Transfection Protein Binding Scavenger Receptors, Class B Virus Internalization Gene Knockdown Techniques Hep G2 Cells |
Rights: | © 2010 Eyre et al. 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 credited. |
DOI: | 10.1371/journal.ppat.1001130 |
Published version: | http://dx.doi.org/10.1371/journal.ppat.1001130 |
Appears in Collections: | Aurora harvest 5 Molecular and Biomedical Science publications |
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hdl_62449.pdf | Published version | 2.45 MB | Adobe PDF | View/Open |
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