Autophagy is initiated by the assembly of a pre-autophagosomal structure referred to as the phagophore initiation site, primarily near the endoplasmic reticulum (ER). This process depends on the Unc51-like kinase complex and the PI3KC3 complex I, which synthesize the signaling lipid phosphatidylinositol 3-phosphate (PI(3)P). A further critical player in the initial stages of phagophore nucleation and expansion is the lipid scramblase ATG9, which is delivered via ATG9 containing vesicles. Endophilin A (EndoA) and synaptojanin-1 (Synj1) are involved in the recycling of ATG9 vesicles. A complex consisting of ATG5, ATG12, and ATG16L1 contributes to autophagosome formation by conjugating ATG8 family members (i.e., LC3 and GABARAP proteins) to phosphatidylethanolamine in the phagophore membrane. Sealed autophagosomes can form autolysosomes upon fusion with lysosomes or signaling organelles (amphisomes) upon fusion with Rab7-positive late endosomal/multivesicular bodies organelles (LE/MVBs). Autophagosome formation intersects with endocytosis and the sorting of proteins and lipids from early endosomes (EEs) to recycling endosomes (REs) or late endosomes (LEs) for degradation guided by small Rab GTPases. In neurons, LE/MVBs are transported retrogradely to the soma via dynein, where they fuse with degradative lysosomes to form endolysosomes. Amphisomes are formed through the fusion of LE/MVBs with autophagosomes, a crucial step that enables autophagosomes to acquire motors for retrograde transport. Upon reaching the soma, these organelles ultimately fuse with acidic lysosomes to form autolysosomes, facilitating cargo degradation.
