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.
Institute of Infection Medicine, Molecular Medical Virology, University of Kiel, D-24105 Kiel, Germany.
Stephanie
S
Schaedler
Janis
J
Krause
Kiyoshi
K
Himmelsbach
Monica
M
Carvajal-Yepes
Franziska
F
Lieder
Karin
K
Klingel
Michael
M
Nassal
Thomas S
TS
Weiss
Sabine
S
Werner
Eberhard
E
Hildt
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