The role of PTEN - HCV core interaction in hepatitis C virus replication

Qi Wu,Paul Mellor,Zhubing Li,Deborah H Anderson,Qiang Liu,Yan Zhou

doi:10.1038/s41598-017-03052-w

Qi Wu, Paul Mellor + Show 4 more

Open Access

https://doi.org/10.1038/s41598-017-03052-w

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Abstract

Hepatitis C virus (HCV) infection leads to severe liver diseases including hepatocellular carcinoma (HCC). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumour suppressor, is frequently mutated or deleted in HCC tumors. PTEN has previously been demonstrated to inhibit HCV secretion. In this study, we determined the effects of PTEN on the other steps in HCV life cycle, including entry, translation, and replication. We showed that PTEN inhibits HCV entry through its lipid phosphatase activity. PTEN has no effect on HCV RNA translation. PTEN decreases HCV replication and the protein phosphatase activity of PTEN is essential for this function. PTEN interacts with the HCV core protein and requires R50 in domain I of HCV core and PTEN residues 1–185 for this interaction. This interaction is required for PTEN-mediated inhibition of HCV replication. This gives rise to a reduction in PTEN levels and intracellular lipid abundance, which may in turn regulate HCV replication. HCV core domain I protein increases the lipid phosphatase activity of PTEN in an in vitro assay, suggesting that HCV infection can also regulate PTEN. Taken together, our results demonstrated an important regulatory role of PTEN in the HCV life cycle.

Highlights

More than 185 million people are estimated to be infected by hepatitis C virus (HCV) worldwide[1], leading to severe liver diseases such as hepatocellular carcinoma (HCC)
Because the aa. 1–185 fragment contains the phosphatase domain of PTEN, these data indicated that the protein and/or lipid phosphatase activities are required for inhibiting Hepatitis C virus (HCV) RNA accumulation
The expression of wild-type or mutant PTEN proteins, demonstrated by Western blotting (Fig. 1b), had no effects on cell viability as measured by MTT assay (Fig. 1c). These results suggest that PTEN negatively regulates HCV RNA levels after viral infection

Summary

Introduction

More than 185 million people are estimated to be infected by hepatitis C virus (HCV) worldwide[1], leading to severe liver diseases such as hepatocellular carcinoma (HCC). Viral RNAs are packaged into nucleocapsids followed by particle maturation and secretion after envelope acquisition It is the nucleocapsid protein, HCV core has many regulatory functions[4], and is associated with the development of HCC in a transgenic mouse model[5]. Another study showed that HCV infection is associated with less nuclear PTEN that favors HCV replication, suggesting a possible role of PTEN in regulating HCV replication[22] This is supported by additional studies demonstrating that HCV core and NS5A proteins downregulate PTEN protein levels[23,24,25,26]. We showed that PTEN inhibits HCV entry and replication, but has no effect on HCV RNA translation.

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