Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis

Figure 1

Proposed model for the interplay between HCV infection and ROS production, Nrf2 signaling, and autophagy. (1) Under homeostatic conditions, Keap1 sequesters Nrf2 in the cytosol, where it mediates proteasomal degradation of Nrf2. (2) HCV infection induces ER stress and alters ER calcium homeostasis. (3) The uptake of calcium in the mitochondria triggers ROS formation. (4) Oxidant stress induced by HCV infection induces the phosphorylation of p62 and autophagy. (5) Consequently, phosphorylated p62 increases its binding to Keap1, thereby releasing Nrf2 from the Keap1-Nrf2 complex. (6) Free Nrf2 is trapped via delocalized sMaf proteins that are associated with NS3 at the replication complex on the cytoplasmic face of the ER, (7) and thus preventing its translocation to the nucleus to induce antioxidant defenses, which in turn favors the release of viral particles. (8) In addition, HCV-induced sequestration of Nrf2 at the replication complex is core dependent, but how the core participates in this process remains unclear.