Hepatitis C Virus Impairs the Induction of Cytoprotective Nrf2 Target Genes by Delocalization of Small Maf Proteins

Abstract

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). Nrf2/ARE-regulated genes are crucial for the maintenance of cellular integrity. Hepatitis C virus inhibits the induction of ARE-regulated genes, but neither induction nor inhibition of ARE-regulated gene expression affects HCV replication directly. In HCV-replicating cells the core protein triggers the delocalization of sMaf proteins from the nucleus to the replicon complex. Here sMafs bind to NS3. The extranuclear sMaf proteins prevent Nrf2 from entry in the nucleus and thereby inhibit the induction of Nrf2/ARE-regulated genes. This results in the decreased expression of cytoprotective genes. Consistent with this finding, the elimination of ROI is impaired in HCV-replicating cells as demonstrated by elevated protein oxidation or 8-OH-dG formation, reflecting DNA damage. In conclusion, these data identified a novel mechanism of Nrf2 regulation and suggest that the HCV-dependent inhibition of Nrf2/ARE-regulated genes confers to the HCV-associated pathogenesis by elevation of intracellular ROI that affect integrity of the host genome and regenerative processes. Hepatitis C virus (HCV)2 infection results in chronic hepatitis in more than 70% of infected individuals. At present more than 170 million people are persistently infected with HCV worldwide.

Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

“…In line with this observation, we found ALR expression induced in HBV-infected, but not in HCV-infected, cells in vitro and in vivo (Figures 4, 5), which is in agreement with some recent findings reporting a HCVdependent inhibition of Nrf2/AREregulated genes (11). In addition, it was reported that Nrf2 protects from toxininduced liver injury and fibrosis (9), which seems to be contradictory to chronic HBV infection as a causative factor for liver fibrosis, cirrhosis or HCC.…”

“…Activation of Nrf2 followed by expression of ARE-regulated genes was not only shown for chemopreventive and antioxidant agents, but also reported to be mediated by hepatitis B virus (HBV) (10), while hepatitis C virus (HCV) inhibits Nrf2 activation (11). Therefore, we analyzed the potential impact of HBV and HCV infection on ALR expression in vitro and in vivo.…”

“…Interestingly, infection of hepatocytes with hepatitis C virus does not activate Nrf2 and inhibits AREregulated gene expression. (11). Liver regeneration is a process regulated by a variety of molecules of which ALR gains great attention because hepatotrophic ALR supports the process of liver regeneration after partial hepatectomy (12,13), and exerts beneficial effects in models of hepatic failure (14,15) and liver fibrosis (16).…”

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

“…4e7 Several mechanisms normally protect the liver from alcoholic injury, and these include antioxidant enzymes, such as superoxide dismutase 8 and thioredoxin. 9 HCV can impair antioxidant defenses by decreasing activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) 10 and heme oxygenase-1, 11 two important components of the antioxidant response, and these have been postulated to play a role in ethanol-HCV synergy. 11 Understanding the mechanisms by which these occur could, therefore, lead to novel prophylactic and therapeutic approaches to alcoholic liver disease.…”

Differential expression of NADPH oxidase-2 (Nox-2) and nuclear factor-erythroid 2-related factor 2 (Nrf2) transcripts in peripheral blood mononuclear cells isolated from dengue patients

“…This is not surprising as similar results were seen in OFI group, but in contrast, during DOD the Nox-2 gene expression was found to increase in dengue cases whereas no such hike was observed in OFI, which makes us to assume if the increase in Nox-2 during DOD is 'specific' for dengue infection. Monica et al [4] studied that during Hepatitis C virus infection delocalization of sMAF proteins caused the formation of Nrf-2-sMAF complex which in turn blocked Nrf2 translocation and ultimately caused transcriptional inactivation of detoxifying enzymes. This could be a possible mechanism for down regulated Nrf2 expression during day of admission.…”