HCV-induced autophagy and innate immunity

Abstract

The interplay between autophagy and host innate immunity has been of great interest. Hepatitis C virus (HCV) impedes signaling pathways initiated by pattern-recognition receptors (PRRs) that recognize pathogens-associated molecular patterns (PAMPs). Autophagy, a cellular catabolic process, delivers damaged organelles and protein aggregates to lysosomes for degradation and recycling. Autophagy is also an innate immune response of cells to trap pathogens in membrane vesicles for removal. However, HCV controls the autophagic pathway and uses autophagic membranes to enhance its replication. Mitophagy, a selective autophagy targeting mitochondria, alters the dynamics and metabolism of mitochondria, which play important roles in host antiviral responses. HCV also alters mitochondrial dynamics and promotes mitophagy to prevent premature cell death and attenuate the interferon (IFN) response. In addition, the dysregulation of the inflammasomal response by HCV leads to IFN resistance and immune tolerance. These immune evasion properties of HCV allow HCV to successfully replicate and persist in its host cells. In this article, we discuss HCV-induced autophagy/mitophagy and its associated immunological responses and provide a review of our current understanding of how these processes are regulated in HCV-infected cells.

Keywords: HCV; STING; autophagy; inflammasome; interferons; mitophagy; oxidative stress.

Figure 1

HCV inhibits the innate immune response. HCV proteins can directly inhibit the innate immune response. NS3/4A plays multiple roles in blocking the host innate immune response. It cleaves MAVS on MAM to block the RIG-I signaling pathway and TRIF to inhibit the TLR3 signaling pathway. NS4B can also disrupt TLR3-mediated IFN signaling by inducing the degradation of TRIF via caspase-8. Other HCV proteins had also been shown to regulate and restrict the production of IFNs and their antiviral signaling: E2 induces SOCS1 and SOCS3; NS3/4A sequesters STING to inhibit the activation of TBK1; NS5A sequesters MyD88 to inhibit TLR signaling; and NS5B induces and activates PKR to inhibit the expression of IFNs and ISGs. HCV also usurps the antiviral activity of autophagy and uses it for its own replication. It not only utilizes the autophagic membranes as the sites for its RNA replication and the production of infectious HCV particles, but also manipulates autophagy to regulate type I IFN response by promoting the autophagic degradation of IFNAR1, TNFR1, and TRAF6, important signal transducers for the activation of NF-κB and the expression of pro-inflammatory cytokines. HCV-induced mitophagy also regulates innate immune response by clearing mitochondrial DAMPs, namely mtROS and mtDNA, and damaged mitochondria themselves, which otherwise would activate the cGAS/STING/TBK1 pathway to induce the expression of IFNs. Mitophagy also inhibits premature apoptotic cell death and promotes HCV persistence. RC: HCV RNA replication complex. The mitochondria-associated membrane (MAM) is boxed and enlarged in the inset to reveal the Ca²⁺ transporter IP3R.

Figure 2

Interplay between HCV-induced autophagy and host innate immune response. HCV-induced autophagy removes DAMPs to inhibit the formation of inflammasomes and hence pyroptosis. HCV-induced autophagic degradation of TNFR1 also inhibits the activation of caspase-8 and apoptosis. However, host cells in response to HCV infection also express TNF-α and IFNAR2 (also see Figure 1 ). TNF-α at a low concentration causes the generation of ROS to initiate autophagy. However, it, at a high concentration, can also put a halt on the completion of autophagy via caspase-8-mediated cleavage of p62, ultimately activating the cGAS/STING/TBK1 pathway and apoptosis. TNF-α-induced cleavage of p62 also disrupts Nrf2 signaling, which is activated by HCV to induce the expression of antioxidant genes to alleviate oxidative stress. HCV also delays the maturation of autophagosomes by inducing the expression of Rubicon for the accumulation of autophagosomes to support its RNA replication, which can also lead to the accumulation of DAMPs. Mitochondrial dynamics are closely related to the regulation of innate immune response. On the other hand, mitochondrial fusion supports inflammasome activation and pro-survival pathways that, if prolonged, can contribute to tumorigenesis. On the other hand, mitochondrial fission, which is coupled with mitophagy and promoted by HCV, supports the formation of MAM which can serve as the platform to mediate IFN response. RC: HCV replication complex.