FIGURE 1.

Molecular aspects of phagophore biogenesis and autophagy initiation. This scheme summarizes in a simplified way the main steps associated with membrane remodeling events leading to phagophore assembly. (A) The de novo biogenesis of the pre-autophagosomal phagophore (also called the isolation membrane) occurs at the ER-associated omegasome and membrane(s) source(s) interface. The phagophore maturation implies cargoes (specific, such as mitochondria, lipid droplets, protein aggregates, bacteria, etc., and non-specific) capture, physical disassembly from the membrane source, and closure, through fission of limiting membrane, which leads to double membrane autophagosome formation. (B) At the omegasome and membrane source interface, the stress-induced ULK1 autophagic complex is locally recruited and in turn allows the direct activation and membrane binding of the PI3KC3 complex, notably composed of VPS34 (the lipid kinase), Beclin1, and ATG14L. Membrane fueling and de novo assembly initiate future phagophore biogenesis, via membrane(s) and lipid delivery (dashed arrows), including lipids from ATG9-positive vesicles. Concomitantly, the presence of VPS34 leads to PI3P local synthesis, a necessary step for membrane flagging and for major ATG recruitment to pre-autophagosomal membrane. Via interaction with the PI3P-binding WIPI2, and via a direct anchoring to PI3P-positive membranes, the ATG16L1 master regulator allows the targeting of the ATG5–12 complex to the membrane, which in turn, with the help of cytosolic ATGs, promotes the local lipidation of LC3 protein at the surface of the future phagophore.