Fig. 1.

Steps of autophagy pathway activation. The biogenesis of autophagosomes requires the ordered intervention of autophagy-regulated (ATG) proteins that act on different modules. Some of these modules are shown on the figure, including the ULK1complex (ULK1/ATG13/FIP200/ATG101) and PI3K complex (Beclin 1/ATG14/calss III PI3K) in the initiation of phagophore formation. During starvation or rapamycin treatment, mTOR is inhibited, leading to ULK1 dephosphorylation and activation of autophagy. Then, the phagophore nucleation is mediated by a complex involving PI3K. (a) The elongation of phagophore is mediated by two ubiquitin-like conjugation systems that together promote the assembly of the ATG12/ATG5/ATG16L complex and the processing of LC3. This molecule is cleaved by the protease ATG4 to generate LC3-I, which is then activated by ATG7, transferred to ATG3 (a second E2 ubiquitin-like enzyme) and conjugated to PE. The lipidated form of LC3-I (LC3-II) is attached to both faces of the phagophore membrane. This step is characterized by membrane bending and increase in size of the phagophore through addition of membrane, which incorporate cytoplasmic components, such as mithocondria, ER, macromolecules, etc. (b) The elongation step ended off with closure of the autophagosome. In the maturation step, fusion of autophagosomes with lysosomes is required for the formation of autolysomes where the substrates are degraded.