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Exp Mol Med. 2016 Nov 11;48(11):e270. doi: 10.1038/emm.2016.98.

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

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Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
Institute for Biochemistry CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Institute of Experimental Internal Medicine, Medical Faculty of the Otto-von-Guericke-University, Magdeburg, Germany.
Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Laboratory of Molecular Biology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Berlin Institute of Health, Berlin, Germany.
Friedrich Loeffler Institute for Medical Microbiology, University Medicine Greifswald, Greifswald, Germany.


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+ 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 the β1i/LMP2, β2i/MECL-1 and β5i/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.

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