Atg5Atg12Atg16L1

The Atg5-Atg12-Atg16L1 complex is a core assembly of the autophagy machinery in many eukaryotic cells. It comprises the covalently linked Atg5-Atg12 conjugate bound to Atg16L1, forming a heterotrimer that can assemble into higher-order, filamentous structures. In mammals, Atg16L1 provides a scaffolding function through its coiled-coil domain, localizing to sites of autophagosome formation such as the phagophore or isolation membrane where it helps define the site of autophagy initiation.

The complex serves as an E3-like component of the LC3 (ATG8) lipidation pathway. By coordinating the actions of the E2-like enzyme Atg3 and LC3 family proteins, it promotes the conjugation of LC3 to phosphatidylethanolamine on the growing membrane. This LC3-PE conjugation is essential for membrane expansion and closure of the autophagosome and is tightly dependent on proper assembly of the Atg5-Atg12-Atg16L1 complex.

Localization and function: The Atg5-Atg12 conjugate binds Atg16L1 to form a stable scaffold that associates with the expanding phagophore. Atg16L1 can oligomerize into multimers that project from the membrane surface, concentrating LC3 lipidation at discrete membrane regions and thereby regulating the progression of autophagosome formation.

Regulation and significance: The complex is essential for canonical autophagy; its disruption blocks LC3 lipidation and autophagosome formation, compromising cellular homeostasis. Variants in Atg16L1 have been linked to autoimmune and inflammatory diseases, such as Crohn’s disease, underscoring the physiological importance of this complex.