title: Hepatitis C Virus NS5A Protein Triggers Oxidative Stress by Inducing NADPH Oxidases 1 and 4 and Cytochrome P450 2E1.
abstract: Replication of hepatitis C virus (HCV) is associated with the induction of oxidative stress, which is thought to play a major role in various liver pathologies associated with chronic hepatitis C. NS5A protein of the virus is one of the two key viral proteins that are known to trigger production of reactive oxygen species (ROS). To date it has been considered that NS5A induces oxidative stress by altering calcium homeostasis. Herein we show that NS5A-induced oxidative stress was only moderately inhibited by the intracellular calcium chelator BAPTA-AM and not at all inhibited by the drug that blocks the Ca(2+) flux from ER to mitochondria. Furthermore, ROS production was not accompanied by induction of ER oxidoreductins (Ero1), H2O2-producing enzymes that are implicated in the regulation of calcium fluxes. Instead, we found that NS5A contributes to ROS production by activating expression of NADPH oxidases 1 and 4 as well as cytochrome P450 2E1. These effects were mediated by domain I of NS5A protein. NOX1 and NOX4 induction was mediated by enhanced production of transforming growth factor β1 (TGFβ1). Thus, our data show that NS5A protein induces oxidative stress by several multistep mechanisms.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Smirnova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Ivanova
authors.affiliation: CRCL, INSERM U1052, CNRS 5286, Université de Lyon, 151 Cours A. Thomas, 69424 Lyon Cedex, France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Valuev-Elliston
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Furkat
authors.initials: F
authors.lastname: Mukhtarov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Kochetkov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ivanov
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004790:Enzyme Induction; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D007477:Ions; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis*; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D000072417:Protein Domains; D017382:Reactive Oxygen Species / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D002118:Calcium; D051546:Cyclooxygenase 2; D019392:Cytochrome P-450 CYP2E1; D007477:Ions; D008562:Membrane Glycoproteins; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D017361:Viral Nonstructural Proteins; C405327:ERO1A protein, human; C402799:NOX1 protein, human; C498910:NOX4 protein, human; C485767:ERO1B protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase