Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins

Cadwell, Ken; Debnath, Jayanta

Subversion during viral replication and transmission. Growing evidence supports that viruses use LC3 + membranes to exit host cells via exocytic pathways analogous to secretory autophagy (Fig. 2) . Infections by poliovirus and coxsackievirus B (CVB), two nonenveloped RNA viruses, result in the formation of LC3 + double membrane vesicles in an ATG-dependent manner, which serve as scaffolds for viral replication complexes (Jackson et al., 2005; Wong et al., 2008) . Instead of degradation in the lysosome, sequestered virions are released from cells within a membrane coat through a process termed autophagosome-mediated exit without lysis (Fig. 2 A; Taylor et al., 2009) . The "envelope" acquired during egress shields virion clusters from immune recognition and aids entry into neighboring cells (Bird et al., 2014; Chen et al., 2015b) . Consistent with these studies that an autophagy-like process is required for viral replication and spread, ATG5 deletion in pancreatic acinar cells of mice leads to a 2,000-fold reduction in CVB replication and protection from pancreatitis (Alirezaei et al., 2012) . In addition to these picornaviruses, lipidated LC3 also contributes to the envelopment and exocytosis of certain herpesviruses during lytic infection. Epstein-Barr virus and varicella-zoster virus acquire LC3-conjugated membranes during envelope acquisition in the cytosol, which can be detected in purified virions (Fig. 2 B; Nowag et al., 2014; Buckingham et al., 2016) . Accordingly, inhibiting LC3 lipidation via ATG12 or ATG16L1 knockdown impairs viral exit and results in the accumulation of viral DNA in the cytosol (Nowag et al., 2014) . Finally, influenza A virus (IAV) encodes an ion channel protein, matrix protein 2, that blocks lysosomal degradation of the virion and facilitates viral egress through binding and redirecting LC3-II to the plasma membrane. Notably, although the improved filamentous budding of IAV is dependent on ATG conjugation pathways that lipidate LC3, the overall infectious virus production remains intact (Fig. 2 C; Gannagé et al., 2009; Beale et al., 2014) .