Hepatitis C virus and autophagy

Abstract

Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses.

Figure 1. Illustration of the autophagic pathway

Beclin-1, p150 and hVps34, which are the three core components of PI3KC3, is important for the initiation of autophagy. ATG5, ATG12 and ATG16L, which form a complex, are important for the elongation of phagophores and the formation of autophagosomes. LC3-I and LC3-II are the non-lipidated and lipidated LC3, respectively. The lipidation of LC3, which enables LC3 to localize to autophagosomes, is mediated by ATG4, ATG7 and ATG3. Autophagosomes mature by fusing with lysosomes to form autolysosomes, in which the cargos of autophagosomes are digested for recycling.

Figure 2. Roles of Rubicon and UVRAG in the maturation of autophagosomes in HCV-infected cells

In the normal autophagic pathway, UVRAG facilitates the fusion between autophagosomes and lysosomes to form autolysosomes. The induction of Rubicon by HCV in the early stage of infection inhibits the UVRAG activity and the fusion between autophagosomes and lysosomes. This leads to the accumulation of autophagosomes. The induction of UVRAG in the late stage of HCV infection overcomes the inhibitory effect of Rubicon and results in the maturation of autophagosomes.

Figure 3. HCV proteins and the autophagic pathway

Both HCV core and NS4B proteins could induce the ER stress and activate the UPR, which has been known to induce autophagy. The HCV p7 protein could bind to Beclin-1, although it is unclear whether this binding plays any role in HCV-induced autophagy. The HCV NS3/4A protease could bind to mitochondria-associated IRGM, which plays an important role in HCV-induced autophagy. HCV NS4B could form a complex with Rab5, hVps34 and Beclin-1, which are important regulatory factors for autophagy. HCV NS5A could upregulate the expression of Beclin-1 via NS5ATP9. HCV NS5B could bind to ATG5, which, as illustrated in Figure 1, is conjugated to ATG12 and associated with ATG16L and important for the elongation of phagophores and the formation of autophagosomes.

Figure 4. Autophagy and the IFN response to HCV infection

HCV viral RNA is recognized by RIG-I, which activates MAVS to induce the expression of type I IFNs. The HCV NS3/4A protease cleaves MAVS to disrupt the RIG-I signaling pathway and blocks the induction of IFN-β and ISGs. The ATG5-ATG12 conjugate can bind to RIG-I and MAVS to inhibit their activities. HCV-induced autophagy also inhibits the RIG-I signaling pathway, although it is unclear whether this inhibition is mediated by the ATG5-ATG12 conjugate. In the presence of IFN-β, autophagy can mediate the degradation of HCV core and NS3/4A proteins.