Fig. 3

Schematic pathways of mammalian autophagy. In macroautophagy, the initiation of autophagy begins with the formation of the phagophore assembly site (PAS) and signals the activity of the vacuolar protein sorting 34 (VPS34) complex. Further nucleation requires a class III PI3K complex, which is composed of VPS34, PI3K and beclin-1. PE- conjugated LC3 (LC3-PE) is necessary for autophagic membrane expansion, recognition of autophagic substances, and fusion of autophagosomes with lysosomes. The resulting autophagosomes fuse with endocytosis and lysosomal compartments, ultimately leading to the formation of autolysosome. In microautophagy, the substrate is directly swallowed by the boundary of the lysosomal membrane. Then, the sequestration of cargo forms a lumenal vesicle by the protrusion and/or invagination of the vacuolar membrane. This vesicle is subsequently degraded by vacuolar hydrolases releasing simple decomposition products. In chaperone-mediated autophagy, the substrate with the pentapeptide motif KFERQ is selectively recognized by the heat shock cognate 70 kDa protein (HSC70) molecular chaperone and translocates to the lysosome in a LAMP2A-dependent manner. Proteins with exposed KFERQ or KFERQ-like motifs are recognized and bound by HSC70. The complex then localizes to the lysosomal membrane where the multimerization of LAMP2A allows the formation of aconitum to delivery the protein into the lysosomal lumen, a process facilitated by the lumenal chaperone HSP90