Figure 1.

Model for selective autophagy in mammalian cells. Autophagosome formation is initiated (nucleation step) by the ULK1 complex and the class III PtdIns 3-kinase complex located at the phagophore. Additional ATG proteins are required for growth of the phagophore (elongation step), that depends on two Ub-like conjugation reactions. First, conjugation of ATG12 to ATG5 results in the formation of an oligomeric complex between the ATG12-ATG5 conjugate and ATG16L. This complex then acts as an E3 ligase assisting the E2 ATG3 in the lipidation of ATG8 family proteins at the phagophore. Selective autophagy depends on binding of substrates to the inner surface of the growing phagophore, and this can be achieved by cargo receptors that are associated both with the substrate and with lipidated ATG8 family proteins anchored to the phagophore. Aggregation of the substrate and/or cargo receptor is required for efficient sequestration. Closure results in the formation of a double-membrane autophagosome. Fusion of autophagosomes with late endosomes or lysosomes (maturation step) is then required for the formation of autolysomes where the substrates are degraded.