The core Atg machinery also entails two ubiquitin-like proteins, Atg12 and Atg8/microtubule-associated protein 1 (MAP1)-light chain 3 (LC3), and their respective, partially overlapping, conjugation systems [44] [45] [46] (Figure 1 ). Atg12 is conjugated to Atg5 through the activity of the Atg7 (E1like) and the Atg10 (E2-like) enzymes. The Atg12-Atg5 conjugate then interacts with Atg16, which oligomerizes to form a large multimeric complex. Atg8/LC3 is cleaved at its C terminus by the Atg4 protease to generate the cytosolic LC3-I with a C-terminal glycine residue, which is then conjugated to phosphatidylethanolamine (PE) in a reaction that requires Atg7 and the E2-like enzyme Atg3. This lipidated form of LC3 (LC3-II) is attached to both faces of the phagophore membrane. Once the autophagosome is completed, Atg4 removes LC3-II from the outer autophagosome surface. These two ubiquitination-like systems appear to be closely interconnected. On one hand, the multimeric Atg12-Atg5-Atg16 complex localizes to the phagophore and acts as an E3-like enzyme, determining the site of Atg8/LC3 lipidation [47, 48] . On the other hand, the Atg8/LC3 conjugation machinery seems to be essential for the optimal functioning of the Atg12 conjugation system. In Atg3-deficient mice, Atg12-Atg5 conjugation is markedly reduced, and normal dissociation of the Atg12-Atg5-Atg16 complex from the phagophore is delayed [49] . Some evidences suggest that these two conjugation systems also function together during the expansion and closure of the phagophore. For example, overexpression of an inactive mutant of Atg4 inhibits the lipidation of LC3 and leads to the accumulation of a number of nearly complete autophagosomes [47] . While controversial [50] , it has been postulated that Atg8/LC3 also possesses fusogenic properties, thus mediating the assembly of the autophagic membrane [51, 52] .