Figure 2.

When cellular energy is sufficient, mammalian target of rapamycin complex 1 (mTORC1) becomes activated and phosphorylates each member of the ULK complex to prevent autophagy induction. In the case of glucose absence or cellular stress conditions, AMP-activated protein kinase (AMPK) becomes activated to initiate autophagic flux. This flux starts with the formation of the ULK complex consisting of ATG13, ULK1/2 and FIP200 (a ULK-interacting protein). The activity of mTORC1 is prohibited, non-phosphorylated ATG13, ULK1/2 and FIP200 forms a complex and, as a result, autophagy is started. The initiation of phagophore formation is achieved with the gathering of the ATG14, Beclin 1, VPS34, VPS15, and AMBRA proteins to generate the VPS34 complex. This also affects the further continuation of autophagic activity with downstream constituents. This takes place with the help of two ubiquitin-like conjugation systems. The first system comprises of ATG12 protein binding. Firstly, ATG7, which is linked to ubiquitin-activating enzyme E1, activates ATG12. Then, with the conjugation of ATG10 linked to ubiquitin-activating enzyme E2, ATG5 and ATG16, a huge protein complex is formed to contribute to the progression of the autophagosome. Similarly, in the second system, with the help of ATG4 protein, LC3 is modified to LC3-I. Then, LC3-I is attached to phosphatidylethanolamine (PE) to form LC3-II-PE catalyzed by ATG7 linked to E1, and ATG3 linked to E2. LC3-II-PE binds the membrane surface of the autophagosome and helps the attachment of adaptor proteins. When the phagophore formation is completed, it is named as a mature autophagosome. After fusion of the lysosome and autophagosome, an autolysosome is formed and it leads the degradation of the materials, recycles the nutrients and metabolites to supply energy (pro-survival) and triggers the autophagic cell death (pro-death).