Hepatitis B Virus Induces Expression of Antioxidant Response Element-regulated Genes by Activation of Nrf2

• Published in: The Journal of biological chemistry Vol. 285; no. 52; pp. 41074 - 41086
• Main Authors: Schaedler, Stephanie, Krause, Janis, Himmelsbach, Kiyoshi, Carvajal-Yepes, Monica, Lieder, Franziska, Klingel, Karin, Nassal, Michael, Weiss, Thomas S., Werner, Sabine, Hildt, Eberhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antioxidants - metabolism; Antiviral Agents - pharmacology; Gene Expression; Gene Expression Regulation; Hep G2 Cells; Hepatitis B - genetics; Hepatitis B - metabolism; Hepatitis B virus; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Hepatitis Virus; Humans; Interferon-alpha - pharmacology; Interferon-gamma - pharmacology; Mice; Mice, Knockout; Molecular Bases of Disease; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Response Elements; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Regulation; Viral Regulatory and Accessory Proteins; Transcription Regulation; Gene Expression; Hepatitis Virus; Oxidative Stress; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.145862

The expression of a variety of cytoprotective genes is regulated by short cis-acting elements in their promoters, called antioxidant response elements (AREs). A central regulator of ARE-mediated gene expression is the NF-E2-related factor 2 (Nrf2). Human hepatitis B virus (HBV) induces a strong activation of Nrf2/ARE-regulated genes in vitro and in vivo. This is triggered by the HBV-regulatory proteins (HBx and LHBs) via c-Raf and MEK. The Nrf2/ARE-mediated induction of cytoprotective genes by HBV results in a better protection of HBV-positive cells against oxidative damage as compared with control cells. Furthermore, there is a significantly increased expression of the Nrf2/ARE-regulated proteasomal subunit PSMB5 in HBV-positive cells that is associated with a decreased level of the immunoproteasome subunit PSMB5i. In accordance with this finding, HBV-positive cells display a higher constitutive proteasome activity and a decreased activity of the immunoproteasome as compared with control cells even after interferon α/γ treatment. The HBV-dependent induction of Nrf2/ARE-regulated genes might ensure survival of the infected cell, shape the immune response to HBV, and thereby promote establishment of the infection.