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.
Highlights
It is estimated that approximately 170 million people worldwide are infected with hepatitis C virus (HCV); a major cause of serious liver disease
The recent development of the retroviral HCV pseudoparticle system (HCVpp), in which HCV E1E2 glycoproteins are assembled onto retroviral cores [3,4,5], and the infectious HCV cell culture (HCVcc) system, in which the full viral lifecycle is recapitulated in cell culture [6,7,8], have allowed in-depth analysis of the HCV entry process
Hepatitis C virus (HCV) infection is a major cause of serious liver disease, with approximately 170 million people infected worldwide
Summary
It is estimated that approximately 170 million people worldwide are infected with hepatitis C virus (HCV); a major cause of serious liver disease. At present there is strong evidence to suggest that the essential HCV entry factors include the tetraspanin CD81 [5,9,10,11], the class B scavenger receptor SR-BI [9,12,13,14], and the tight-junction proteins claudin-1 and occludin [15,16,17,18,19,20]. Considering that these proteins may comprise the complete set of essential HCV entry factors [18], it still remains to be determined what the relative involvement of each of these entry factors is and, beyond expression, what secondary factors influence the contribution of these proteins to HCV entry
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