Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner.
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.
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.
In Soo
IS
Oh
Institute for Biochemistry CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Kathrin
K
Textoris-Taube
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Pil Soo
PS
Sung
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Wonseok
W
Kang
Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Xenia
X
Gorny
Institute of Experimental Internal Medicine, Medical Faculty of the Otto-von-Guericke-University, Magdeburg, Germany.
Thilo
T
Kähne
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Seon-Hui
SH
Hong
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Young Joon
YJ
Choi
Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Clemens
C
Cammann
Institute of Experimental Internal Medicine, Medical Faculty of the Otto-von-Guericke-University, Magdeburg, Germany.
Michael
M
Naumann
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Jong Hoon
JH
Kim
Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Su-Hyung
SH
Park
Laboratory of Molecular Biology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Ook Joon
OJ
Yoo
Institute for Biochemistry CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
Peter M
PM
Kloetzel
Institute for Molecular and Clinical Immunology, Medical Faculty of the Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.|Friedrich Loeffler Institute for Medical Microbiology, University Medicine Greifswald, Greifswald, Germany.
Ulrike
U
Seifert
Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Eui-Cheol
EC
Shin
D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D019892:eIF-2 Kinase / Q000276:immunology*
D012333:RNA, Messenger; D007371:Interferon-gamma; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase; D046988:Proteasome Endopeptidase Complex