Abstract
Hepatitis C virus (HCV) is a positive-strand RNA virus replicating in a membranous replication organelle composed primarily of double-membrane vesicles (DMVs) having morphological resemblance to autophagosomes. To define the mechanism of DMV formation and the possible link to autophagy, we conducted a yeast two-hybrid screening revealing 32 cellular proteins potentially interacting with HCV proteins. Among these was the Receptor for Activated Protein C Kinase 1 (RACK1), a scaffolding protein involved in many cellular processes, including autophagy. Depletion of RACK1 strongly inhibits HCV RNA replication without affecting HCV internal ribosome entry site (IRES) activity. RACK1 is required for the rewiring of subcellular membranous structures and for the induction of autophagy. RACK1 binds to HCV nonstructural protein 5A (NS5A), which induces DMV formation. NS5A interacts with ATG14L in a RACK1 dependent manner, and with the ATG14L-Beclin1-Vps34-Vps15 complex that is required for autophagosome formation. Both RACK1 and ATG14L are required for HCV DMV formation and viral RNA replication. These results indicate that NS5A participates in the formation of the HCV replication organelle through interactions with RACK1 and ATG14L.
Highlights
Liver diseases caused by hepatitis C virus (HCV) constitute a significant health burden worldwide
Hepatitis C virus (HCV), a prototype member of the Flaviviridae family, rearranges intracellular membranes to construct replication organelles composed primarily of double-membrane vesicles (DMVs) which are morphologically similar to autophagosomes
Nonstructural protein 5A (NS5A), which is essential for HCV replication, induces DMV formation
Summary
Liver diseases caused by hepatitis C virus (HCV) constitute a significant health burden worldwide. Antiviral drugs allow HCV elimination in the vast majority of infected individuals, it is becoming increasingly clear that global eradication will require a vaccine that, is not yet available. HCV is a Hepacivirus genus member, which belongs to the Flaviviridae family [3]. The HCV genome is a 9.6 kb long single-stranded RNA of positive sense encoding 10 or more viral proteins. The viral proteins are synthesized as a polyprotein via an internal ribosome entry site (IRES) residing in the 50 untranslated region (50UTR). The polyprotein is proteolytically cleaved into functional proteins by cellular and virus-encoded proteinases [4]
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