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. 2019 Sep 19;20(18):4659. doi: 10.3390/ijms20184659

Figure 1.

Figure 1

Interference of hepatitis C virus (HCV) with the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)/ Keap1-signaling pathway. Lines labelled with an “X” represent blocked processes, dotted lines describe indirect processes, solid lines describe translocations or direct effects.HCV is associated with oxidative stress in liver cells that results in increased levels of ROS. ROS in HCV infected hepatocytes can be related to ER-stress and the UPR, mitochondrial dysregulation, Ca2+ redistribution, activation of NADPH oxidases and enhanced expression of CYP2E1 and Ero1α. The increased ROS-levels further trigger phosphorylation of p62 on Ser349 that activates Nrf2. Based on the impaired Nrf2/Keap1-signaling pathway in HCV-infected cells, the oxidative stress cannot be compensated. This mechanism is based on a core-mediated delocalization of sMaf-proteins from the nucleus to the ER-associated RCs, where they are trapped by binding to NS3. As a consequence, the delocalized sMaf-proteins bind to Nrf2 and prevent the translocation of Nrf2 into to the nucleus resulting in impaired expression of cytoprotective genes. In addition NS5A interferes with Nrf2-activation via a crosstalk with the MAPK-signaling cascade. NS5A recruits cRaf to the ER-associated RCs resulting in activation of cRaf and NS5A phosphorylation. However, despite cRaf activation no activation of the MAPK signaling cascade could be observed resulting in impaired Nrf2-activation. The elevated ROS-levels further interfere with mechanisms involved in liver regeneration. Impaired Nrf2 activation results in a decreased tyrosine phosphorylation and enhanced serine/threonine-phosphorylation of IRS-1 and -2 that may contribute to the development of insulin resistance and impaired liver regeneration. However, the mechanisms regulating increased ROS-levels in HCV-infected cells are conflicting. UPR, unfolded protein response; NOX, NADPH oxidase; CYP2E1, cytochrome P450 E1; Ero1α, ER oxidoreductin 1α; MAPK, mitogen-activated protein kinase; IRS1/2, insulin receptor substrate; IR, insulin receptor; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; JNK, c-Jun-N-terminal kinase; NQO1, NAD(P)H:quinone oxidoreductase 1; GPx, glutathione peroxidase; γ-GCS, γ-glutamylcysteine synthetase.