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Viruses 2015, 7(6), 2745-2770; doi:10.3390/v7062745

HCV Core Protein Uses Multiple Mechanisms to Induce Oxidative Stress in Human Hepatoma Huh7 Cells

1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia
2
Latvian Biomedical Research and Study Center, Ratsupites 1, Riga LV1067, Latvia
3
Inserm U1052, Cancer Research Center of Lyon, University of Lyon, 151, Cours A Thomas, 69424 Lyon Cedex, Lyon, France
4
DevWeCan Laboratories of Excellence Network (Labex), Lyon F-69000, France
5
Ivanovsky Institute of Virology, Gamaleya str. 16, Moscow 123098, Russia
6
Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Ratsupites 5, Riga LV-1069, Latvia
7
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobelsvägen 16, Stockholm 17177, Sweden
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Andrew Mehle
Received: 21 April 2015 / Revised: 12 May 2015 / Accepted: 26 May 2015 / Published: 29 May 2015
(This article belongs to the Section Animal Viruses)
View Full-Text   |   Download PDF [1971 KB, uploaded 29 May 2015]   |  

Abstract

Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGFβ1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS). The same fragment also induced the expression of cyclo-oxygenase 2, which, however, made no input into ROS production. Amino acids 37–191 of HCV core up-regulated the transcription of a ROS generating enzyme cytochrome P450 2E1. Furthermore, the same fragment induced the expression of endoplasmic reticulum oxidoreductin 1α. The latter triggered efflux of Ca2+ from ER to mitochondria via mitochondrial Ca2+ uniporter, leading to generation of superoxide anions, and possibly also H2O2. Suppression of any of these pathways in cells expressing the full-length core protein led to a partial inhibition of ROS production. Thus, HCV core causes oxidative stress via several independent pathways, each mediated by a distinct region of the protein. View Full-Text
Keywords: hepatitis C virus; oxidative stress; reactive oxygen species; NADPH oxidase; transforming growth factor; cytochrome P450; ER oxidoreductin hepatitis C virus; oxidative stress; reactive oxygen species; NADPH oxidase; transforming growth factor; cytochrome P450; ER oxidoreductin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ivanov, A.V.; Smirnova, O.A.; Petrushanko, I.Y.; Ivanova, O.N.; Karpenko, I.L.; Alekseeva, E.; Sominskaya, I.; Makarov, A.A.; Bartosch, B.; Kochetkov, S.N.; Isaguliants, M.G. HCV Core Protein Uses Multiple Mechanisms to Induce Oxidative Stress in Human Hepatoma Huh7 Cells. Viruses 2015, 7, 2745-2770.

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