Hepatitis C Virus Exploits Death Receptor 6-mediated Signaling Pathway to Facilitate Viral Propagation

Trang T D Luong,Soon B Hwang,Yun-Sook Lim,Dong-Jo Shin,Giao V Q Tran

doi:10.1038/s41598-017-06740-9

Trang T D Luong, Soon B Hwang + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-06740-9

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Journal: Scientific Reports	Publication Date: Jul 25, 2017
Citations: 7	License type: open-access

Affiliation: Hallym University, Institut Pasteur Korea

Abstract

The life cycle of hepatitis C virus (HCV) is highly dependent on host proteins for virus propagation. By transcriptome sequencing analysis, we identified host genes that were highly differentially expressed in HCV-infected cells. Of these candidates, we selected Death receptor 6 (DR6) for further characterization. DR6 is an orphan member of the tumor necrosis factor receptor superfamily. In the present study, we demonstrated that both mRNA and protein levels of DR6 were increased in the context of HCV replication. We further showed that promoter activity of DR6 was increased by HCV infection. By employing promoter-linked reporter assay, we showed that HCV upregulated DR6 via ROS-mediated NF-κB pathway. Both mRNA and protein levels of DR6 were increased by NS4B or NS5A. However, NS5A but not NS4B specifically interacted with DR6. We showed that HCV modulated JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner. Interestingly, Akt signaling cascade was regulated by protein interplay between DR6 and NS5A. Silencing of DR6 expression resulted in decrease of infectious HCV production without affecting viral entry, replication, and translation. Together, these data indicate that HCV modulates DR6 signaling pathway for viral propagation and may contribute to HCV-mediated pathogenesis.

Highlights

We demonstrated that promoter activities of Death receptor 6 (DR6) were gradually increased during the course of hepatitis C virus (HCV) infection compared to mock-infected cells (Fig. 1E, lower panel)
It has been reported that mRNA levels of DR6 in rat hepatocytes were dramatically increased during liver regeneration21. mRNA level of DR6 was moderately upregulated in peripheral blood mononuclear cells of chronic HCV patients[22]
We demonstrated that both mRNA and protein levels of DR6 were upregulated by HCV

Summary

Introduction

Activation of NF-κB and NF-AT signaling pathways transiently enhance DR6 expression in both activated human CD4+ and CD8+ T cells[11]. Functional involvement of DR6 in viral infection has not been demonstrated yet. Using RNA-Seq analysis, we recently identified 30 host genes which were upregulated in HCV-infected cells[12]. We demonstrated that HCV infection upregulated DR6 expression via ROS-mediated NF-κB pathway. We showed that HCV modulated JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner. DR6 was required for the production of infectious HCV. These data suggest that DR6 is required for HCV propagation and involved in HCV-associated pathogenesis

Methods

Results

Conclusion