Divergent Roles of Autophagy in Virus Infection

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

Most positive-strand RNA viruses re-shape the endomembrane system in order to create membrane- [71] . This reorganization of intracellular membranes frequently requires autophagy and was first described for the poliovirus [72] . By using thin section EM analysis of infected cells, double-membrane vesicles (DMVs) were detected that are characteristic of autophagosome-like structures (Figure 4) . These structures stained positive for the viral protein 2BC, and they did not co-fractionate with markers of other known organelles, highlighting their distinct nature [72] . Expression of the viral proteins 2BC and 3A resulted in the lipidation of LC3 and induced the formation of autophagosome-like DMVs [72] . These properties are not unique for poliovirus, but have been found for several other picornaviruses such as CVB3, enterovirus 71 (EV71) and foot-andmouth disease virus (FMDV) [42, 73, 74] . Cells infected with these viruses also contain accumulations of DMVs that are not only morphologically similar, but also contain LC3 as well as viral replicase proteins ( Figure 4) . However, it is important to note that the membrane composition of picornaviral replication sites is heterogeneous, and other mechanisms have been suggested to explain their formation and composition [75, 76] . Importantly, key elements of the secretory pathway are involved in the biogenesis of these membranous structures, including COP-II coated vesicles, Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor-1 (GBF-1), ADP-ribosylation factor 1 (ARF1) and phosphatidylinositol 4- [77] . Finally, it was also shown that poliovirus, EV71 and FMDV can replicate in the absence of autophagy, although in some cases virus production was decreased [18, 42, 73, 78] . These studies suggest that autophagosomes, per se, are dispensable for the biogenesis of viral replication sites, although some autophagy proteins can contribute to their morphological heterogeneity. Autophagy is known to exert diverse proviral functions during viral infection. Autophagosomes have been proposed provide a membrane platform for viral replication complexes or to mediate virus assembly and release. Furthermore, viruses can trigger selective autophagy to degrade either lipids (lipid droplets) for energy production during viral replication or to subvert immune responses by selectively degrading key regulatory molecules. The mechanistic details related to proviral functions of autophagy are discussed in the text.