Hepatitis C virus comes for dinner: How the hepatitis C virus interferes with autophagy

Figure 2 Schematic model of the crosstalk between hepatitis C virus and autophagy. Hepatitis C virus (HCV) replication occurs in replication complexes that assemble at the ER resulting in ER stress and induction of an unfolded protein response (UPR). The UPR activates three signaling pathways (ATF6, IRE1, PERK) and finally autophagy. In addition the UPR can be triggered by NS4B through activation of the IRE1 and ATF6 pathway as NS4B interferes with Ca²⁺ homeostasis resulting in elevated reactive oxidant species (ROS). Elevated ROS levels trigger phosphorylation of p62 on Ser351 (p-p62) following subsequent activation of Nrf2. NS4B further forms a complex with Rab5, Vps34 and Beclin-1 stimulating an autophagic response. In addition the human immunity-associated GTPase family M (IRGM) protein interacts with NS3/4A and the autophagosomal protein Atg5, Atg10 and LC3 that trigger autophagy. Activation of autophagy favors HCV replication and plays a crucial role in release of viral particles. Here, the interaction of TIP47 and activated Rab9 (aRab9) to the particles is essential. Moreover, HCV-induced autophagy impairs innate immunity and favors cell survival via inhibition of apoptosis.