title: Analysis of the Domains of Hepatitis C Virus Core and NS5A Proteins that Activate the Nrf2/ARE Cascade.
abstract: The hepatitis C virus (HCV) triggers a chronic disease that is often accompanied by a spectrum of liver pathologies and metabolic alterations. The oxidative stress that occurs in the infected cells is considered as one of the mechanisms of HCV pathogenesis. It is induced by the viral core and NS5A proteins. It is already known that both of these proteins activate the antioxidant defense system controlled by the Nrf2 transcription factor. Here, we show that this activation is mediated by domain 1 of the NS5A protein and two fragments of the core protein. In both cases, this activation is achieved through two mechanisms. One of them is mediated by reactive oxygen species (ROS) and protein kinase C, whereas the other is triggered through ROS-independent activation of casein kinase 2 and phosphoinositide 3-kinase. In the case of the HCV core, the ROS-dependent mechanism was assigned to the 37-191 a.a. fragment, while the ROS-independent mechanism was assigned to the 1-36 a.a. fragment. Such assignment of the mechanisms to different domains is the first evidence of their independence. In addition, our data revealed that intracellular localization of HCV proteins has no impact on the regulation of the antioxidant defense system.
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: O A
authors: OA
authors: Smirnova
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: O N
authors: ON
authors: Ivanova
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: F Sh
authors: FS
authors: Mukhtarov
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: V L
authors: VL
authors: Tunitskaya
authors: Riga Stradins University, Dzirciema Street, 16, LV-1007, Riga, Latvia.
authors: J
authors: J
authors: Jansons
authors: Riga Stradins University, Dzirciema Street, 16, LV-1007, Riga, Latvia ; N. F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Gamaleya str., 18, Moscow, 123098, Russia.
authors: M G
authors: MG
authors: Isaguliants
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: S N
authors: SN
authors: Kochetkov
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str., 32, Moscow, 119991, Russia.
authors: A V
authors: AV
authors: Ivanov
keywords: Hepatitis C virus; Nrf2; oxidative stress; regulation; transcription factor