The Human Autophagy Core Complexes

The autophagy core machinery carries out the fundamental reactions of autophagosome biogenesis across all forms of bulk and selective macroautophagy. In humans, the core complexes consist of the ULK1 complex (ULK1C), the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1), the ATG8 proteins and the ATG8ylation machinery, the phosphatidylinositol 3-phosphate (PI3P)-sensing WIPI proteins, the lipid transporter ATG2, and the lipid scramblase and initiation scaffold ATG9. These complexes form a web of interactions that can be initiated by clustering of the FIP200 subunit of ULK1C but also by PI3KC3-C1 or WIPI2. Upon autophagy induction, these interactions are intensified by feed-forward signaling loops. These loops are amplified by WIPI-PI3P interactions and the conjugation of ATG8 proteins to the membrane by the ATG12-ATG5-ATG16L1 complex. Autophagosomes are seeded by ATG9 vesicles, which accrue initiation machinery on their surface and dock onto a PI3P-positive domain of the endoplasmic reticulum known as the omegasome. The omegasome contact site is the focal point for autophagosome growth, which is fed by lipid transport through the ATG2 bridge-like lipid transporter. The core complexes function in a dynamic manner, which makes autophagy vulnerable to stalling when dynamism fails. Disassembly and dissociation of the machinery, which is promoted at least in part by ULK1, is likely to be as important as assembly.