Autophagy in HCV Replication and Protein Trafficking

Abstract

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses.

Keywords: HCV RNA replication; autophagosome biogenesis; autophagy; hepatitis C virus; innate immunity; mitophagy; protein trafficking.

Figure 1

Direct and indirect mechanisms of hepatitis C virus (HCV)-induced autophagy. HCV proteins can directly induce autophagy by interacting with cellular proteins that regulate autophagy. HCV can also indirectly induce autophagy by inducing the ER stress to trigger the unfolded protein response (UPR) or by inducing the production of reactive oxygen species (ROS) and oxidative stress. See text for details.

Figure 2

Biogenesis of autophagosomes induced by HCV. Phagophores induced by HCV originate from the ER membranes. The HCV RNA replication complex as well as its associated lipid rafts and caveolin-1 (Cav-1) become associated with phagophores through an unknown mechanism. Phagophores subsequently undergo homotypic fusion in a process dependent on syntaxin 7 (STX7) to form autophagosomes. During these processes, apolipoprotein E (ApoE) becomes associated with autophagosomes and is delivered by autophagosomes to the HCV assembly site to interact with the HCV E2 envelope protein. Some of the autophagosomes may also fuse with lysosomes to form autolysosomes to result in the autophagic degradation of ApoE.