Divergent Roles of Autophagy in Virus Infection

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

Among these, PERK and ATF6 function as inducers of autophagy, while IRE1 acts as a negative regulator [47] . It was recently shown that HCV infection can induce ER stress and activate all three sensors of UPR [47] . siRNA-mediated silencing of any of the three UPR signaling proteins not only resulted in a significant reduction of LC3-II abundance, but also inhibited HCV replication, arguing that all three UPR signaling pathways are required for HCV-induced autophagy [36] (Figure 2 ). The exact mechanism by which HCV mediates induction of autophagy via ER stress and UPR remains to be investigated. In contrast, a very recent study by Mohl et al provided evidence that HCV-induced autophagy is independent of UPR [49] . Subgenomic replicons expressing nonstructural (NS3-5B) proteins, as well as a mutant virus lacking the envelope glycoproteins, potently induced autophagy in the absence of detectable UPR [49] . Thus, taking both studies together [36, 49] , it is unclear how autophagy is induced in HCV infection. Recent studies with other related flaviviruses, such as Dengue virus (DENV) and Modoc virus, showed that virus infection induced autophagy [50] . In fact, expression of the replicase protein NS4A from either virus was sufficient for autophagy induction via UPR [50] (Figure 2 ). However, the impact of these viral proteins on autophagic flux remains to be determined. Lastly, DNA viruses can also induce autophagy via ER-stress and UPR-related pathways. In the case of varicella-zoster virus (VZV) infection, it was demonstrated that virus-induced ER stress and UPR response precede autophagosome formation [51] . The authors show that ER stress upon VZV infection is due to abundant VZV glycoprotein biosynthesis, which in turn triggers to UPR and thus, autophagy to maintain cellular homeostasis.