title: HCV core protein uses multiple mechanisms to induce oxidative stress in human hepatoma Huh7 cells.
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 TGF\(\upbeta\)1-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 1\(\upalpha\). 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.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. aivanov@yandex.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ivanov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. o.smirnova.imb@gmail.com.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Smirnova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. irina-pva@mail.ru.
authors.forename: Irina Y
authors.initials: IY
authors.lastname: Petrushanko
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. olgaum@yandex.ru.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Ivanova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. ilkzkil@gmail.com.
authors.forename: Inna L
authors.initials: IL
authors.lastname: Karpenko
authors.affiliation: Latvian Biomedical Research and Study Center, Ratsupites 1, Riga LV1067, Latvia. kate@biomed.lu.lv.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Alekseeva
authors.affiliation: Latvian Biomedical Research and Study Center, Ratsupites 1, Riga LV1067, Latvia. irina@biomed.lu.lv.
authors.forename: Irina
authors.initials: I
authors.lastname: Sominskaya
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. aamakarov@eimb.ru.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Makarov
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, 151, Cours A Thomas, 69424 Lyon Cedex, Lyon, France. birke.bartosch@inserm.fr.|DevWeCan Laboratories of Excellence Network (Labex), Lyon F-69000, France. birke.bartosch@inserm.fr.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia. kochet@eimb.ru.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Kochetkov
authors.affiliation: Ivanovsky Institute of Virology, Gamaleya str. 16, Moscow 123098, Russia. maria.issagouliantis@ki.se.|Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Ratsupites 5, Riga LV-1069, Latvia. maria.issagouliantis@ki.se.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobelsvägen 16, Stockholm 17177, Sweden. maria.issagouliantis@ki.se.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Isaguliants
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004252:DNA Mutational Analysis; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D013481:Superoxides; D006861:Hydrogen Peroxide; C405327:ERO1A protein, human; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C056558:CYBB protein, human; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D002118:Calcium
keywords: ER oxidoreductin; NADPH oxidase; cytochrome P450; hepatitis C virus; oxidative stress; reactive oxygen species; transforming growth factor