Fig. 2.

Regulation and execution of the autophagosomal-lysosomal degradation pathway. Two ubiquitin-like conjugation systems are involved in the regulation of autophagy. ATG12, a ubiquitin-like protein, is covalently bound to ATG5 by the E1 and E2 enzymes ATG7 and ATG10, respectively. In parallel, LC3 is cleaved by ATG4, primed by the E1 and E2 enzymes ATG7 and ATG3 to be covalently linked to the lipid phosphatidylethanolamine (PE) by the E3 ligase complex ATG12/5/16 to generate the processed, lipid-bound form of LC3, LC3-II. LC3-II and the ATG12/5/16 complex act together in the elongation and finally closure of the phagophore. LC3-II also acts as anchor on the inner membrane for adaptor proteins such as p62 that recognize ubiquitinated substrates, e.g., misfolded proteins or damaged organelles. On aged or dysfunctional mitochondria, PINK1 localizes to the outer membrane, where it is recognized and ubiquitinated by the E3 ubiquitin ligase parkin. Ubiquitinated PINK1 recruits autophagy receptors such as p62 and renders the mitochondria attractive for degradation by autophagy (“mitophagy”). After closure, the autophagosome with its cargo is primed for fusion with lysosomes, which is accompanied by removal and recycling of LC3-II by ATG4. The resulting autolysosome degrades the cargo and releases the components (amino acids, lipids) for metabolic and energy consuming processes. Substrates selected for lysosomal degradation by the signal sequence KFERQ can reach their destination also by binding to the chaperone HSC70 and LAMP2A-mediated direct import into the lysosomal lumen (chaperone-mediated autophagy; CMA). The kinase LRRK2 is involved in regulation of CMA and mitophagy, the latter via direct interaction with parkin. Ub: ubiquitin