Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis

Abstract

With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

“…Alternatively, Nrf2 activity can be controlled by a proteasomal degradation mechanism mediated by the serine/threonine protein kinase glycogen synthase kinase 3 (GSK-3) and the E3 ligase adapter β-TrCP [ 25 ]. β-TrCP is a substrate receptor for S-phase kinase-associated protein 1 (Skp1)-Cul1-Rbx1/Regulator of cullins-1 (Roc1) ubiquitin ligase complex that targets Nrf2 for ubiquitination and proteasomal degradation, while GSK-3 is an important protein related with Keap1-independent Nrf2 stabilization and regulation.…”

“…Active GSK-3 can phosphorylate Nrf2 in its Neh6 domain to facilitate the recognition of Nrf2 by β-TrCP, promoting Nrf2 protein degradation [ 12 ]. Lastly, an additional degradation system can regulate Nrf2 activation through the E3 ubiquitin ligase Hrd1, which is part of the inositol-required protein 1 pathway of the unfolded protein response [ 25 ]. A schematic illustration of the aforementioned Keap1 and Nrf2 domains and regulatory mechanisms is depicted in Figure 1 .…”

“…Several studies correlated cellular stress with HCV infection, and persistence of oxidative stress during HCV replication has been widely observed [ 89 ]. The HCV-related proteins, as well as non-structural and structural proteins, were found to trigger production of ROS [ 3 , 9 , 25 , 41 ].…”

“…Chronic infection with HBV causes liver inflammation and can promote fibrosis, which can ultimately lead to cirrhosis and HCC [ 25 , 89 ]. Proteins of HBV (HBx) were reported to induce the formation of ROS, and both regulatory proteins of HBV (HBx and LHBs) activate NF-κB, which leads to induction of proinflammatory cytokines [ 25 ].…”

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

“…Taken together, there are contrasting reports about the implication of Nrf2 in viral hepatitis infection. On one hand, Nrf2 induction inhibits virus replication through its target genes (i.e., HO-1); on the other hand, HBV- and HCV-positive cells might exploit the protective function of Nrf2, and this could contribute to liver tumorigenesis [ 55 ].…”