Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation of Nrf2.
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.
Schaedler
Stephanie
S
Institute of Infection Medicine, Molecular Medical Virology, University of Kiel, D-24105 Kiel, Germany.
Krause
Janis
J
Himmelsbach
Kiyoshi
K
Carvajal-Yepes
Monica
M
Lieder
Franziska
F
Klingel
Karin
K
Nassal
Michael
M
Weiss
Thomas S
TS
Werner
Sabine
S
Hildt
Eberhard
E
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D000975:Antioxidants; D000998:Antiviral Agents; D016898:Interferon-alpha; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007371:Interferon-gamma; C088874:PSMB5 protein, human; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse