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Oxidative Medicine and Cellular Longevity
Volume 2016 (2016), Article ID 8341937, 10 pages
http://dx.doi.org/10.1155/2016/8341937
Research Article

Hepatitis C Virus NS5A Protein Triggers Oxidative Stress by Inducing NADPH Oxidases 1 and 4 and Cytochrome P450 2E1

1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia
2CRCL, INSERM U1052, CNRS 5286, Université de Lyon, 151 Cours A. Thomas, 69424 Lyon Cedex, France

Received 28 September 2015; Revised 3 February 2016; Accepted 1 March 2016

Academic Editor: Cinzia Signorini

Copyright © 2016 Olga A. Smirnova et al. 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.

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 Ca2+ 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.