Fig. 3

Macroautophagy pathways. The autophagic process is divided into five stages including initiation, phagophore nucleation, phagophore formation, autophagosome-lysosome fusion, and cargo degradation in autolysosomes. Signals activating macroautophagy usually originate from starvation, hypoxia, oxidative stress, and stress of the endoplasmic reticulum (ER). These signals trigger the activity of Unc-51-like kinase 1 (ULK1) complex (consisting of ULK1, FIP200, ATG13, and ATG101), which then starts phosphorylation of components of the class III PI3K (PI3KC3) complex I (consisting of VPS34, VPS15, Beclin1, ATG14L, and NRBF2) enabling nucleation of the phagophore. VPS34 produces phosphatidylinositol-3-phosphate (PI3P) allowing the recruitment of autophagy-associated PI3P-binding proteins such as DFCP1 and WIPI mediating the initial stages of autophagosome formation by associating ATG2A stably to PI3P-containing areas. Expansion of the phagophore requires the ATG2A-WIPI complex mediating ER–phagophore association and establishing the transfer of lipid membranes from the ER and the vesicles to the phagophore. WIPI was also shown to bind ATG16L1, thus recruiting the ATG12–ATG5–ATG16L1 complex. Elongation of autophagosomes requires the ubiquitin-like conjugation system managing the orchestrated activity of ATG proteins and LC3 (microtubule-associated protein light chain 3) and/or GABARAP. The ATG12–ATG5–ATG16L1 complex enhances the final connection of phosphatidylethanolamine (PE) molecules resulting in the formation of membrane-bound LC3-II and/or GABARAP-PE. Cellular membranes, including the mitochondrial membrane, the plasma membrane, recycling endosomes, and the Golgi complex, contribute to the elongation of the phagophore by providing membrane material. Elongation of the phagophore gives rise to double-layered vesicles called autophagosomes. In addition to managing autophagy induction in complex I, complex VPS34-Beclin1 has also a role in the fusion of autophagosomes with lysosomes as complex II. UVRAG competes with ATG14L for binding to Beclin1. When bound to Beclin1, UVRAG stimulates RAB7 GTPase activity and autophagosome fusion with lysosomes. Autophagosome-lysosome fusion is managed by Syntaxin-17 (STX17) on autophagosomes, VAMP8 on lysosomes, and by accessory proteins such as ATG14 and homotypic fusion, and protein sorting (HOPS) tethering complex