Fig. 1: Autophagy processes.
a Macroautophagy is the only autophagy process that involves another organelle, the autophagosome. It is induced when mTORC1 becomes inactivated upon dissociation from the lysosome. After the phagophore matures into a double-membraned autophagosome, the lysosome fuses with the outer autophagosomal membrane in a SNARE-dependent manner. Fusion is facilitated by tethering factors that bind to proteins on the autophagosome (e.g. LC3) and the lysosome (e.g. RAB7). Lysosomal enzymes degrade the inner autophagosomal membrane and sequestered material. Tubules extend from autolysosomes by KIF5B binding to clathrin-organised PI(4,5)P2 clusters on the autolysosomal membrane and moving away from the autolysosome on microtubules. The tubules are eventually cleaved from the autolysosome by Dyn2, generating new lysosomes. b Chaperone-mediated autophagy (CMA) involves the direct uptake of proteins with the KFERQ(-like) motif into lysosomes via a translocation complex consisting of LAMP2A monomers on the lysosomal membrane that is stabilised by GFAP and luminal HSP90. CMA substrates are delivered to LAMP2A by cytosolic HSC70 and other cytosolic chaperones. Substrate translocation is assisted by lysosomal HSC70. c RN/DNautophagy is the direct delivery of nucleic acids into lysosomes via the nucleic acid transporter, SIDT2. LAMP2C binds nucleic acids and potentially passes them to SIDT2 for translocation into the lysosomal lumen. d Microautophagy is the uptake of cytosolic material by invagination of the lysosomal membrane. Although it has been observed in lysosomes since the discovery of this organelle, mechanistic details are still scarce. Microautophagy in endosomes is more well-understood. Endosomal microautophagy substrates contain KFERQ(-like) motifs and are recognised by cytosolic HSC70 to be delivered to endosomes, where HSC70 binds to phosphatidylserine. Membrane deformation and eventually scission of intralumenal vesicle from the endosomal membrane are executed by the ESCRT machinery.
