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LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.

ABSTRACT: BACKGROUND:Hepatitis C virus infection is one of the leading causes of end stage liver diseases. The innate immune response slows down viral replication by activating cytokines such as type I interferon (IFN-?/?), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. Recently, leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) was reported contributing to the production of interferon-? in macrophages. OBJECTIVES:The aim of this study was to assess the role of LRRFIP1 in induction of IFN-? and inhibition of HCV infection in hepatocytes. MATERIALS AND METHODS:Induction of IFN-? by LRRFIP1 in Huh7 and Huh7.5.1 was determined by real-time PCR and western blotting in vitro. Inhibition of HCV replication by LRRFIP1 overexpression in hepatocytes was assessed. RESULTS:LRRFIP1 increased the expression of IFN-? in hepatocytes with or without HCV infection. Induction of IFN-? by LRRFIP1 was enhanced with the presence of hepatitis C virus. Overexpression of LRRFIP1 in hepatocytes inhibited HCV replication. However, HCV infection did not regulate intracellular expression of LRRFIP1. CONCLUSIONS:LRRFIP1 and its mediated production of type I interferon play a role in controlling HCV infection. The findings of this study provide new target for HCV treatment and contribute to development of anti-HCV drugs.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4451274 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.

Liu Yuan Y Zou Ziying Z Zhu Bing B Hu Zonghai Z Zeng Ping P Wu Lijuan L

Hepatitis monthly 20150523 5

<h4>Background</h4>Hepatitis C virus infection is one of the leading causes of end stage liver diseases. The innate immune response slows down viral replication by activating cytokines such as type I interferon (IFN-α/β), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. Recently, leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) was reported contributing to the production of interferon-β in macrophages.<h4>Objectives</h4>The aim of th ...[more]

PMID: 26045710

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Project description:Peste des petits ruminants virus (PPRV) infection causes highly contagious and severe disease in domestic and wild ruminants. It is widely reported that PRRV infection causes considerable innate immunosuppression in its host and promotes viral replication. However, how does the host rescue the innate immune response to counteract this immunosuppression during viral replication is poorly understood. The goat fetal fibroblasts (GFFs) have been commonly used as host-original cells to investigate the pathogenesis of PPRV. To explore the mechanisms of how host counteracts PPRV-mediated innate immunosuppression, a high-throughput quantitation proteomic approach (iTRAQ in conjunction with LC-MS/MS) was used to investigate the proteome landscape of GFFs in response to PPRV infection. Eventually, the proteomic analysis gained 497 up-regulated proteins and 358 down-regulated proteins (PPRV-infected cells versus mock-infected cells). The complement and coagulation cascades, protein digestion and absorption, and cytokine-cytokine receptor interaction pathways were significantly regulated in response to PPRV infection. ErmineJ analysis of the differentially expressed proteins (DEPs) identified the significantly enriched GO categories for response to interferon-gamma and positive regulation of ERK1 and ERK2 cascade. In addition, many immune related proteins, such as interferon gamma, 2'-5'-oligoadenylate synthase-like protein, toll-like receptor 9, toll-like receptor 6, NOD1, plasminogen activator inhibitor 1, and Wnt-5a were significantly upregulated. This suggested that the innate immune response was triggered during PPRV infection in GFFs. We subsequently identified that the E3 ubiquitin ligase FANCL was critically involved in regulation of the innate immune response during PPRV infection. FANCL inhibited PPRV infection by enhancing type I interferon (IFN) and interferon-stimulated genes (ISGs) expression. Further study indicated that FANCL induced type I IFN production by promoting TBK1 phosphorylation, and therefore impairing PPRV-mediated immunosuppression and revealing an antiviral function against PPRV.

Dataset Information

LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.

Publications

LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.

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