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

• Published in: PloS one Vol. 10; no. 3; p. e0119172
• Main Authors: Choi, Jung Eun, Kwon, Jung Hyun, Kim, Jung-Hee, Hur, Wonhee, Sung, Pil Soo, Choi, Sang Wook, Yoon, Seung Kew
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.03.2015; Public Library of Science (PLoS)
• Subjects: Biological response modifiers; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Chronic infection; CXCL10 protein; Cytokines - metabolism; Down-Regulation - drug effects; Down-Regulation - genetics; Dual Specificity Phosphatase 1 - genetics; Gastroenterology; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Silencing; Genotype & phenotype; Health aspects; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatoma; Hospitals; Humans; Infection; Infections; Interferon; Interferons - pharmacology; Internal medicine; Kinases; Liver; Liver cancer; Liver Neoplasms - pathology; MicroRNAs; Myxovirus resistance proteins; Nuclear transport; Phosphatase; Phosphatases; Phosphorylation; Proteases; Protein A; Proteins; Replication; Replicon - genetics; Ribonucleic acid; RNA; RNA, Small Interfering - genetics; Science; Stat1 protein; STAT1 Transcription Factor - metabolism; Transcription; Translocation; Ubiquitin; Ubiquitin-specific proteinase; Ubiquitins - metabolism; USP18 protein; Virus replication; Virus Replication - drug effects; Virus Replication - genetics; Viruses; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119172

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.