Divergent Roles of Autophagy in Virus Infection

Chiramel, Abhilash I.; Brady, Nathan R.; Bartenschlager, Ralf

The induction of autophagy is triggered by a variety of stress stimuli, including nutrient deprivation, ER stress, danger-associated molecular patterns (DAMPs), hypoxia, redox stress and mitochondrial damage. These stimuli involve a diverse range of cellular signals that have overlapping functions in autophagy and the control of other cellular stress responses. Viruses can trigger many of these stimuli during different stages of their replication cycle. For instance, several reports have shown that upon binding to the surface of target cells, some viruses can stimulate autophagy. One example is CD46 (cluster of differentiation 46), a cell surface receptor which is recognized by several viral pathogens, including human herpesvirus 6, adenovirus types B and D, and measles virus [43] (Figure 2 ). In case of the latter, CD46 engagement was shown to be sufficient to induce autophagy; viral binding of CD46 leads to its interaction with GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) ( Figure 2 ), which then associates with the Vps34-Beclin-1 complex, leading to activation of autophagy [43] . While it is not known whether other viruses entering cells via CD46 also induce autophagy, in the case of HIV-1 binding to CD4+, T-cells trigger autophagy, and this is mediated by the C-terminal domain of the fusogenic gp41 subunit of the viral envelope protein [44, 45] . Recent studies with the vesicular stomatitis virus (VSV) demonstrated that virus binding to Drosophila S2 cells was required to induce autophagy [31] , which occurred via down regulation of mTOR activity and inactivation of Akt signaling [31] . Finally, a very recent study demonstrated that VSV-induced autophagy depends on Toll-7 in S2 cells and in adult flies [46] . The authors show that VSV interacted with Toll-7 at the plasma membrane to induce antiviral autophagy independent of the canonical Toll signaling pathway [46] (Figure 2 ). Apart from attachment of the virus particle to the host cell, viral replication itself frequently elicits stress responses, such as ER stress or production of reactive oxygen species (ROS) that induce autophagy [47] . The endoplasmic reticulum (ER) is the major site for protein synthesis. An accumulation of misfolded or unfolded proteins in this compartment results in ER stress and activates an unfolded protein response (UPR) mediated by three ER membrane-associated proteins: PERK (PKR--6) and IRE1 (inositol requiring enzyme 1). All three proteins are normally bound to and inactivated by the chaperone Bip/GRP78 at the side of the ER lumen. When ER stress is triggered, Bip interacts with unfolded luminal proteins, thus leading to the release of PERK, IRE1 and ATF6. PERK mediates the phosphorylation of eukaryotic translation y reducing the load of new proteins in the ER [48] . In addition, PERK phosphoryla activating transcription factor 4 (ATF4) to induce transcription of genes involved in amino acid synthesis and apoptosis [48] . IRE1 is autophosphorylated to function as an endoribonuclease, responsible for the unconventional splicing of the X box-binding protein 1 (XBP1) mRNA. The resulting translation product XBP1 regulates transcription of genes encoding for ER chaperones, biogenesis of phospholipids and components of the ER-associated protein degradation (ERAD) machinery. Finally, activated ATF6 translocates from the ER to the Golgi to undergo cleavage by regulated intramembrane proteolysis (RIP) by site 1 and site 2 proteases. The