Abstract
Development of hepatitis C virus (HCV) infection cell culture systems has permitted the identification of cellular factors that regulate the HCV life cycle. Some of these cellular factors affect steps in the viral life cycle that are tightly associated with intracellular membranes derived from the endoplasmic reticulum (ER). Here, we describe the discovery of erlin-1 protein as a cellular factor that regulates HCV infection. Erlin-1 is a cholesterol-binding protein located in detergent-resistant membranes within the ER. It is implicated in cholesterol homeostasis and the ER-associated degradation pathway. Silencing of erlin-1 protein expression by siRNA led to decreased infection efficiency characterized by reduction in intracellular RNA accumulation, HCV protein expression and virus production. Mechanistic studies revealed that erlin-1 protein is required early in the infection, downstream of cell entry and primary translation, specifically to initiate RNA replication, and later in the infection to support infectious virus production. This study identifies erlin-1 protein as an important cellular factor regulating HCV infection.
Highlights
Hepatitis C virus (HCV) is an enveloped virus belonging to the Flaviviridae family [1]
In this study we describe the discovery that erlin-1 protein regulates the initiation of hepatitis C virus (HCV) RNA replication, the accumulation of viral proteins and the production of infectious virus, adding erlin-1 to the list of host factors required for efficient HCV infection
We transfected Huh-7 cells with siRNAs targeting erlin-1 or erlin-2 individually, or siRNAs targeting both erlin proteins simultaneously, siRNAs targeting HCV as a positive control and a non-targeting siRNA as a negative control. siRNA transfected cells were inoculated at low multiplicity of infection with a cell culture-adapted HCV virus (D183v) [34] and their susceptibility to infection was assessed by measuring virus production three and five days later
Summary
Hepatitis C virus (HCV) is an enveloped virus belonging to the Flaviviridae family [1]. The HCV genome is around 9.6 kb positive-sensed single-stranded RNA containing a unique long open reading frame (ORF) that encodes a single polyprotein of approximately 3000 amino acids [3]. The 50 and 30 nontranslated regions (NTR), flanking the ORF, contain essential sequences for RNA stability, translation and replication [4,5,6]. A highly structured internal ribosomal entry site located in the 50 NTR drives the translation of the polyprotein that is co- and post-translationally processed by both host and viral proteases leading to the expression of three structural (core, E1 and E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) [7]. HCV entry into hepatocytes starts with the interaction of viral and cellular factors, present in the viral membrane, with several receptors present in the plasma membrane of the hepatocytes
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