Divergent Roles of Autophagy in Virus Infection

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

Autophagy induction involves the coordinated action of several key factors ( Figure 1 ). Among them are members of the Atg8 ubiquitin-like (Ubl) protein family, which include MAP1LC3A (microtubule-associated protein 1 light chain 3A), MAP1LC3B, MAP1LC3C, GABARAP -aminobutyric acid type A [GABA] receptor-associated protein), GABARAPL1 (GABARAP like 1), GABARAPL2 and GABARAPL3, all of which are important for phagophore formation and closure in mammals [15] . In principle, any of the above mentioned Atg8 family proteins can serve as a marker of autophagosomes in mammalian cells, however, conventionally only MAP1LC3B (referred to as LC3 henceforth) is used as marker of autophagosomes in mammalian cells [16, 17] . During autophagosome formation and elongation, the cytosolic LC3, termed LC3-I, is proteolytically cleaved and coupled to phosphatidyl-ethanolamine (PE) to form LC3-II, which is inserted into the autophagosomal membrane [1, 9] . The two main characteristics of autophagy detection is, first, the increase in intracellular levels of LC3-II and, second, the re-localization of evenly distributed cytosolic LC3-I into LC3-II positive punctuate structures, representing autophagosomes [1, 9] . Indeed, infections with a wide range of DNA or RNA viruses increase abundance of autophagosomes or autophagic vesicles in infected cells [18 34] . Furthermore, several electron microscopy-based studies revealed the presence of double-membrane structures that are characteristic of autophagosomes. However, it is important to note that increased amounts of autophagosomes in infected cells can either be due to their enhanced formation or to their accumulation due to a block in their maturation or degradation. Therefore, to understand the reason for increased autophagosome numbers in virus-infected cells, it is important to study the impact of viral infection on autophagic activity or autophagic flux, which is defined as the measurement of the balance between the rate of autophagosome formation and degradation. Assays to measure autophagic activity in mammalian cells have been described in detail in other reviews and, therefore, will only be mentioned here [16, 17] .