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Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

1
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany
2
Bioinformatics and Systems Biology, Faculty of Biology and Chemistry, Justus-Liebig-University, 35392 Giessen, Germany
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School of Biochemistry and Cell Biology, University College Cork, Cork T12 XF62, Ireland
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Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia
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Institute for Virology, Faculty of Veterinary Medicine, Justus-Liebig University, 356392 Giessen, Germany
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Inst. of Biochemistry, Faculty of Biology and Chemistry, Justus-Liebig-University, 35392 Giessen, Germany
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Inst. of Medical Virology, Justus-Liebig-University, National Reference Center for Hepatitis B and D Viruses, Giessen, and German Center for Infection Research (DZIF), partner site Giessen, 35392 Giessen, Germany
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Genevention GmbH, 37079 Göttingen, Germany
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RNA Bioinformatics and High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, 07743 Jena, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1321; https://doi.org/10.3390/ijms20061321
Received: 31 January 2019 / Revised: 6 March 2019 / Accepted: 12 March 2019 / Published: 15 March 2019
(This article belongs to the Special Issue Translational Control)
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Abstract

Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here. View Full-Text
Keywords: HCV; HCC; hepatocellular carcinoma; liver cancer; Warburg effect; ER stress; ribosome profiling; Riboseq; respiratory chain; mitochondria HCV; HCC; hepatocellular carcinoma; liver cancer; Warburg effect; ER stress; ribosome profiling; Riboseq; respiratory chain; mitochondria
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Gerresheim, G.K.; Bathke, J.; Michel, A.M.; Andreev, D.E.; Shalamova, L.A.; Rossbach, O.; Hu, P.; Glebe, D.; Fricke, M.; Marz, M.; Goesmann, A.; Kiniry, S.J.; Baranov, P.V.; Shatsky, I.N.; Niepmann, M. Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling. Int. J. Mol. Sci. 2019, 20, 1321.

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