Figure 1. Scheme of autophagy pathways in the liver.

Schematic depiction of the three types of autophagy that coexist in liver. Macroautophagy is (A) initiated with the formation of the limiting membrane using lipids and proteins from different organelles. Cargo sequestration (B) can occur in bulk or in a selective manner mediated by soluble protein receptors. After engulfment (C) the sealed vesicle (autophagosome) traffics (D) via microtubules and delivers cargo to lysosomes through membrane fusion (E) to form an autolysosome where cargo is degraded by lysosomal hydrolases (F). In chaperone-mediated autophagy (CMA), all substrates carry a pentapeptide (KFERQ-like) recognized (A) by the cytosolic chaperone Hsc70. The substrate-chaperone complex binds (B) to the CMA receptor LAMP-2A at the lysosomal membrane. The substrate must be unfolded (C) before translocation (D) through the multimeric complex formed by LAMP-2A at the lysosomal membrane. A luminal Hsc70 assists in substrate translocation into lysosome where the substrate is finally degraded (E). Microautophagy in liver has been observed in late endosomes where proteins also carrying KFERQ-like motifs are internalized in small microvesicles that form through invagination of the endosomal membrane. As in CMA, the consensus motif allows Hsc70 recognition (A), but in this case the substrate/chaperone complex binds directly to lipids at the endosomal membrane (B). Microvesicles trapping this cargo that form in an ESCRT-dependent manner are internalized (C) into the endosome lumen where degradation takes place (D). Some degradation may also be completed upon endosome/lysosomal fusion. In the case of yeast, direct trapping of lipid droplets by the vacuole (yeast lysosome equivalent) through a microautophagy-like process has been described, but whether or not this process also takes place in mammalian lysosomes requires future investigation.