Atg5Atg12Atg16

The Atg5–Atg12–Atg16 complex is a core assembly in the autophagy pathway. It forms when Atg12 is covalently conjugated to Atg5 in a ubiquitin-like cascade involving the E1-like enzyme Atg7 and the E2-like enzyme Atg10, producing the Atg5–Atg12 conjugate. This conjugate then noncovalently binds to Atg16 (ATG16L1 in mammals) to assemble a multimeric complex that localizes to the expanding autophagosomal membrane, or phagophore, at sites such as the pre-autophagosomal structure. In mammals, the complex is typically described as Atg5–Atg12–Atg16L1, reflecting the main components of the heteromeric assembly.

Functionally, the complex acts as an E3-like ligase to promote the lipidation of Atg8 family proteins (LC3/Atg8) with phosphatidylethanolamine on autophagosomal membranes. This lipidation, carried out with the assistance of the E1 Atg7 and the E2 Atg3, is essential for membrane expansion, cargo recruitment, and the maturation of autophagosomes. The Atg5–Atg12–Atg16 complex therefore serves both as a scaffold that localizes the lipidation machinery to the phagophore and as an enhancer of LC3/Atg8 conjugation efficiency.

Conservation and significance: The Atg5–Atg12–Atg16 complex is conserved from yeast to humans and is indispensable for efficient autophagosome formation. Disruption of complex assembly or function impairs autophagy and is linked to various diseases, including inflammatory conditions where Atg16L1 variants have been implicated.