the sr-bi partner pdzk1 facilitates hepatitis c virus entrysr-bi伙伴pdzk1促进丙型肝炎病毒条目.pdfVIP

The SR-BI Partner PDZK1 Facilitates Hepatitis C Virus Entry Nicholas S. Eyre1,2, Heidi E. Drummer3,4,5, Michael R. Beard1,2* 1 Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia, 2 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia, 3 Burnet Institute, Melbourne, Victoria, Australia, 4 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia, 5 Department of Microbiology, Monash University, Clayton, Victoria, Australia 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 wi