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Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner.

ABSTRACT: By changing the relative abundance of generated antigenic peptides through alterations in the proteolytic activity, interferon (IFN)-?-induced immunoproteasomes influence the outcome of CD8⁺ cytotoxic T lymphocyte responses. In the present study, we investigated the effects of hepatitis C virus (HCV) infection on IFN-?-induced immunoproteasome expression using a HCV infection cell culture system. We found that, although IFN-? induced the transcriptional expression of mRNAs encoding the ?1i/LMP2, ?2i/MECL-1 and ?5i/LMP7 immunoproteasome subunits, the formation of immunoproteasomes was significantly suppressed in HCV-infected cells. This finding indicated that immunoproteasome induction was impaired at the translational or posttranslational level by HCV infection. Gene silencing studies showed that the suppression of immunoproteasome induction is essentially dependent on protein kinase R (PKR). Indeed, the generation of a strictly immunoproteasome-dependent cytotoxic T lymphocyte epitope was impaired in in vitro processing experiments using isolated 20S proteasomes from HCV-infected cells and was restored by the silencing of PKR expression. In conclusion, our data point to a novel mechanism of immune regulation by HCV that affects the antigen-processing machinery through the PKR-mediated suppression of immunoproteasome induction in infected cells.

SUBMITTER: Oh IS

PROVIDER: S-EPMC5133375 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner.

Oh In Soo IS Textoris-Taube Kathrin K Sung Pil Soo PS Kang Wonseok W Gorny Xenia X Kähne Thilo T Hong Seon-Hui SH Choi Young Joon YJ Cammann Clemens C Naumann Michael M Kim Jong Hoon JH Park Su-Hyung SH Yoo Ook Joon OJ Kloetzel Peter M PM Seifert Ulrike U Shin Eui-Cheol EC

Experimental & molecular medicine 20161111 11

By changing the relative abundance of generated antigenic peptides through alterations in the proteolytic activity, interferon (IFN)-γ-induced immunoproteasomes influence the outcome of CD8<sup>+</sup> cytotoxic T lymphocyte responses. In the present study, we investigated the effects of hepatitis C virus (HCV) infection on IFN-γ-induced immunoproteasome expression using a HCV infection cell culture system. We found that, although IFN-γ induced the transcriptional expression of mRNAs encoding th ...[more]

PMID: 27833096

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Project description:Hepatitis C Virus (HCV) infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC). The pivotal role of hepatic stellate cells (HCSs) and extracellular matrix (ECM) in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1-derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha-smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP). These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in HSCs.

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Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner.

Publications

Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner.

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