Autophagy in HCV Infection: Keeping Fat and Inflammation at Bay

Figure 1

A schematic drawing showing the interplay between HCV and autophagy. HCV nonstructural (NS) proteins assemble with the viral genome on the endoplasmic reticulum (ER) membranes to form the replication complex. Viral replication alters ER homeostasis leading to ER stress, which, in turn, activates the unfolded protein response (UPR) through ATF6, IRE1, and PERK proteins. UPR plays a major role in the induction of autophagy, either directly or indirectly by affecting cellular redox balance. In fact, ER stress causes calcium release from ER that results in impaired mitochondrial activity coupled to excessive production of reactive oxygen species (ROS). Damaged mitochondria are thus targeted for degradation via mitophagy. Mitophagy is also stimulated by HCV by activating the mitochondrial fission protein Drp1. Notably, the mitochondrial protein IRGM interacts with both viral and autophagy proteins (ATGs) and is required for autophagy induction. HCV exploits the autophagic process to accomplish different steps of its life cycle such as translation, replication, assembly, and release of lipoviroparticles (LVP). These effects are, at least in part, indirect since autophagy represses the intracellular innate immune pathways, thus inhibiting IFN production. On the other hand, autophagy could also act as defense mechanism against HCV, since when induced by IFN-β causes the degradation of the viral protein NS3/NS4A. Importantly, autophagy is crucial for preventing pathogenesis induced by HCV. Indeed, a type of autophagy selective for lipids (lipophagy) protects cells from an excessive lipid accumulation triggered by HCV (LD: lipid droplets). Moreover, infected cells are more prone to death when autophagy is inhibited. Mitophagy is selectively involved in the control of HCV infection, innate immunity, and cell death (not shown in the figure, see text for details).