Suppression of dual specificity phosphatase I expression inhibits hepatitis C virus replication.

Jung Eun Choi,Pil Soo Sung,Jung Hyun Kwon,Wonhee Hur,Jung-Hee Kim,Seung Kew Yoon,Sang Wook Choi,Sean Bong Lee

doi:10.1371/journal.pone.0119172

Abstract

It was reported that dual specificity phosphatase 1 (DUSP1) is specifically upregulated in the liver of patients with chronic hetpatitis C virus (HCV) infection who do not respond to peginterferon (PegIFN) treatment. Here, we have investigated the role of DUSP1 in HCV replication in hepatoma cells stably expressing the full HCV replicon (FK). DUSP1 was silenced in cells harboring the FK replicon using a lentiviral vector encoding a DUSP1-specific short hairpin RNA (LV-shDUSP1). We demonstrated that knock-down of DUSP1 significantly inhibited HCV RNA and protein expression. Also, DUSP1 silencing enhanced the expression of phosphorylated signal transducer and activator of transcription 1 (phosho-STAT1) and facilitated the translocation of STAT1 into the nucleus. The mRNA expression levels of myxovirus resistance protein A (MxA), 2'-5'-oligoadenylate synthetase 1 (OAS1), ISG15 ubiquitin-like modifier (ISG15), chemokine C-X-C motif ligand 10 (CXCL10), and ubiquitin-specific protease 18 (USP18) were also accelerated by silencing of DUSP1. Furthermore, combined with the IFN treatment, DUSP1 silencing synergistically decreased the levels of HCV RNA. These results suggest that suppression of DUSP1 expression enhances phosphorylation and nuclear translocation of STAT1, resulting in increasing expression of interferon-stimulated genes (ISGs), which synergizes with IFN's antiviral effect against HCV. In conclusion, DUSP1 is involved in the antiviral host defense mechanism against a HCV infection and thus DUSP1 might be a target to treat chronic HCV infection.

Highlights

Hepatitis C virus (HCV) is a major cause of chronic liver disease because chronic HCV infection can progress to liver cirrhosis and hepatocellular carcinoma [1]
To assess the effect of dual specificity phosphatase 1 (DUSP1) silencing on the HCV life cycle, the FK replicon was infected with LV-shDUSP1 particles
We determined whether silencing of DUSP1 affects HCV replication and translation

Summary

Introduction

Hepatitis C virus (HCV) is a major cause of chronic liver disease because chronic HCV infection can progress to liver cirrhosis and hepatocellular carcinoma [1]. Several genes are upregulated in the liver tissue of patients who later do not respond to HCV treatment [10,11,12]. Many of these genes are interferon-stimulated genes (ISGs), whose expression levels are consistent with a link between interferon (IFN) responsiveness and treatment efficacy [10]. The expression levels of a subset of eight genes, including dual specificity phosphatase 1 (DUSP1) and ubiquitin-specific protease 18 (USP18), have previously been used to predict the treatment response of patients with chronic hepatitis C [10]. Silencing USP18 prolongs the phosphorylated state of signal transducer and activator of transcription 1 (STAT1) and enhances the expression of ISGs in response to IFN-α [13]

Methods

Results

Conclusion