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Interferon-? inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection.

ABSTRACT: Viral entry requires co-operative interactions of several host cell factors. Interferon (IFN) and the IFN-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We examined the effect of interferon-? inducible protein 6 (IFI6) against HCV infection in human hepatoma cells. HCV RNA level or infectious foci were inhibited significantly by ectopic expression of IFI6. IFI6 impaired CD81 co-localization with claudin-1 (CLDN1) upon HCV infection or CD81 cross-linking by specific antibody. Activation of epidermal growth factor receptor (EGFR), a co-factor involved in CD81/CLDN1 interactions, was reduced in IFI6 expressing cells in response to HCV infection or CD81 cross linking by antibody, but not by treatment with EGF. Taken together, the results from our study support a model where IFI6 inhibits HCV entry by impairing EGFR mediated CD81/CLDN1 interactions. This may be relevant to other virus entry processes employing EGFR.

SUBMITTER: Meyer K

PROVIDER: S-EPMC4355636 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Interferon-α inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection.

Meyer Keith K Kwon Young-Chan YC Liu Shuanghu S Hagedorn Curt H CH Ray Ratna B RB Ray Ranjit R

Scientific reports 20150311

Viral entry requires co-operative interactions of several host cell factors. Interferon (IFN) and the IFN-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We examined the effect of interferon-α inducible protein 6 (IFI6) against HCV infection in human hepatoma cells. HCV RNA level or infectious foci were inhibited significantly by ectopic expression of IFI6. IFI6 impaired CD81 co-localization with claudin-1 (CLDN1) upon HCV infection o ...[more]

PMID: 25757571

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Project description:Long noncoding RNAs (lncRNAs) play a critical role in the regulation of many important cellular processes. However, the mechanisms by which lncRNAs regulate viral infection and host immune responses are not well understood. We sought to explore lncRNA regulation of hepatitis C virus (HCV) infection and interferon response. We performed RNA sequencing (RNAseq) in Huh7.5.1 cells with or without interferon alpha (IFN?) treatment. Clustered regularly interspaced short palindromic repeats/Cas9 guide RNA (gRNA) was used to knock out selected genes. The promoter clones were constructed, and the activity of related interferon-stimulated genes (ISGs) were detected by the secrete-pair dual luminescence assay. We constructed the full-length and four deletion mutants of an interferon-induced lncRNA RP11-288L9.4 (lncRNA-IFI6) based on predicted secondary structure. Selected gene mRNAs and their proteins, together with HCV infection, in Huh7.5.1 cells and primary human hepatocytes (PHHs) were monitored by quantitative real-time PCR (qRT-PCR) and western blot. We obtained 7,901 lncRNAs from RNAseq. A total of 1,062 host-encoded lncRNAs were significantly differentially regulated by IFN? treatment. We found that lncRNA-IFI6 gRNA significantly inhibited HCV infection compared with negative gRNA control. The expression of the antiviral ISG IFI6 was significantly increased following lncRNA-IFI6 gRNA editing compared with negative gRNA control in Japanese fulminant hepatitis 1 (JFH1)-infected Huh7.5.1 cells and PHHs. We observed that lncRNA-IFI6 regulation of HCV was independent of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. lncRNA-IFI6 negatively regulated IFI6 promoter function through histone modification. Overexpression of the truncated spatial domain or full-length lncRNA-IFI6 inhibited IFI6 expression and increased HCV replication. Conclusion: A lncRNA, lncRNA-IFI6, regulates antiviral innate immunity in the JFH1 HCV infection model. lncRNA-IFI6 regulates HCV infection independently of the JAK-STAT pathway. lncRNA-IFI6 exerts its regulatory function via promoter activation and histone modification of IFI6 through its spatial domain.

Dataset Information

Interferon-? inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection.

Publications

Interferon-α inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection.

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