Recruitment and Activation of a Lipid Kinase by Hepatitis C Virus NS5A Is Essential for Integrity of the Membranous Replication Compartment

Reiss, S., et al. 2011. Cell Host & Microbe. 9, 32–45

Speaker: Sheng- huei Lin Chung  (林張聖彙)             Time: 13:10~14:00, May18, 2011

Commentator: Dr. Kung-Chia Young (楊孔嘉老師)    Place: Room 601

Abstract

Hepatitis C virus (HCV) is a major cause of acute and chronic liver diseases in human. According to previous studies, HCV replicates their genome in the cytoplasm of infected cells with virally encoded enzyme and host factors associated with an endoplasmic reticulum-derived membranous web. It is known that viral nonstructural protein NS4B may induce membranous web formation and the viral genome is copied by the NS5B RNA-dependent RNA polymerase with help of the NS3-4A RNA helicase and NS5A RNA-binding phosphoprotein. However, it is still controversial about a common host factor for HCV replication and the detailed mechanism has not been identified yet. In this study, the authors performed a genome-wide siRNA screen and identified 13 kinases as HCV RNA replication-dependent factors, including PI4KIIIα, as been suggested before. They showed that PI4KIIIα colocalized with HCV RNA replication site and was necessary for replication. To  study the  mechanism  of how PI4KIIIα contributes to viral replication, the authors showed that PI4KIIIα knockdown inhibited viral nonstructural protein-induced membranous web formation. They further showed that  PIP4, a product synthesized by PI4KIIIα, was elevated in HCV-containing cells in vitro and in vivo. Due to PI4P colocalized with viral replication complex in time-dependent experiment, the authors  speculated one or several replicase proteins may recruit the kinase. They showed NS5A domain 1 interacted with PI4KIIIαand surprisingly directly induced its kinase ability. Taken together, this study showed that PI4IIIKα, a host factor, is recruited to HCV replication complex by NS5A, which in turn stimulates its kinase activity. Accumulation of PI4P in these replication complexes may contribute membranous web integrity.

References

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2. Moradpour, D., et al. (2007). Replication of hepatitis C virus. Nature Review. 453-463.