Figure 4.

The process of autophagy. Initiation of autophagy is controlled by the ULK1 complex, followed by activation of the PI3-kinase complex leading to nucleation of the phagophore. Vesicle expansion is governed by two ubiquitin-like conjugation systems: the Atg5-Atg12- Atg16 and Atg8/LC3 pathways. Finally, autophagosomes fuse with lysosomes forming autolysosomes, where breakdown of the autophagic cargo takes place. Selective autophagy can distinguish and direct specific cargos to the lysosome. Autophagy receptors contain a short LIR (LC3-interacting region) sequence responsible for Atg8/LC3 binding. Recognition of ubiquitinylated proteins is mediated by interacting with ubiquitin noncovalently, via an ubiquitin-binding domain (UBA). NIX acts as a mitophagy receptor; it has a LIR motif but lacks an UBA domain and is localized within the mitochondrial outer membrane; this is why ubiquitinylation is not required for NIX-dependent delivery of damaged mitochondria to autophagosomes.