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. 2022 Sep 7;14(18):4351. doi: 10.3390/cancers14184351

Figure 3.

Figure 3

Overview of the general autophagy pathway in mammalian cells. (Bottom) Autophagy can be divided into five major steps: (1) Initiation and nucleation of the double-membrane phagophore, (2) elongation, (3) closure of the phagophore to form the autophagosome, (4) autophagosome-lysosome fusion; and (5) lysosomal degradation and nutrient recycling. (Top left) Upon activation by AMP-activated protein kinase (AMPK), the unc-51-like autophagy activating kinase 1 (ULK1) complex (also known as the preinitiation complex) initiates autophagy by activating the class III phosphatidylinositol 3-kinase (PI3K) complex (also known as the initiation complex) via phosphorylation of Beclin1 and VPS34. Thereafter, the activated class III PI3K complex generates phosphatidylinositol 3-phosphate (PI3P) at the site of nucleation of the phagophore from ER, leading to the binding of PI3P-binding proteins, such as WIPI proteins, that are required for phagophore maturation. (Top middle) ProLC3 is cleaved by ATG4B and to produce LC3-I. Thereafter, LC3-I is conjugated to phosphatidylethanolamine (PE) with a series of ubiquitin-like conjugation reactions that include the E1 ligase (ATG7), E2 ligase (ATG3), and the E3 ligase complex that is composed of ATG12, ATG5, and ATG16L. PE-conjugated LC3, termed LC3-II, is inserted into the phagophore membranes, where LC3-II promotes phagophore elongation and closure. LC3B-II also works as a docking site of autophagy receptor proteins, facilitating the trafficking of their cargos to the autophagosome, a process known as selective autophagy. Multiple inhibitors have been developed so far, which are shown in gray frames. ULK, Unc-51-like kinase; PI3K, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol 3-phosphate; ER, endoplasmic reticulum; WIPI, WD-repeat protein interacting with phosphoinositide; mTORC1, mammalian target of rapamycin complex 1; AMPK, 5′ AMP-activated protein kinase; PE, phosphatidylethanolamine. Figure 3 is adapted from reference [41], the use of which is licensed under a Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/.