Atg12Atg5Atg16L1

The Atg12-Atg5-Atg16L1 complex is a conserved multimeric assembly that coordinates autophagy in mammalian and other eukaryotic cells. It functions as a scaffold on the phagophore, the precursor to the autophagosome, and is required for efficient LC3/Atg8 lipidation and autophagosome formation.

The complex forms through a ubiquitin-like conjugation pathway in which Atg12 is conjugated to Atg5 by the E1-like enzyme Atg7 and the E2-like enzyme Atg10. The Atg12-Atg5 conjugate then binds to Atg16L1, generating a larger Atg12-Atg5-Atg16L1 complex that can oligomerize and associate with developing autophagic membranes.

Functionally, the Atg12-Atg5-Atg16L1 complex acts as an E3-like enzyme to promote Atg3-mediated conjugation of LC3/Atg8 to phosphatidylethanolamine on the isolation membrane. By localizing and organizing the LC3 lipidation machinery, the complex influences membrane expansion, curvature, and closure of the autophagosome, and it participates in canonical and selective autophagy pathways.

Regulation occurs downstream of autophagy initiation signals such as ULK1 and PI3K class III activity. The complex localizes to nascent autophagic membranes and interacts with components that regulate autophagosome biogenesis, including phosphatidylinositol 3-phosphate effectors like WIPI proteins.

Clinical relevance: perturbations in ATG genes, including ATG12, ATG5, and ATG16L1, can impair autophagy. The ATG16L1 T300A variant has been associated with Crohn's disease, highlighting the importance of this complex for immune and intestinal homeostasis. The complex also participates in broader cellular stress responses and pathogen defense.