ATG16L1 membrane recruitment in autophagy.

Autophagy, a highly conserved catabolic pathway in eukaryotes, is essential for cellular survival during starvation and for maintaining cellular homeostasis. Central to autophagy is the de novo formation of double-membrane autophagosomes, which requires the orchestrated action of a set of autophagy-related (ATG) proteins. ATG16L1 is a core autophagy protein involved in distinct phases of autophagosome biogenesis, including membrane remodeling and the formation of phagophore-like membrane cups. It interacts with the ATG12-ATG5 conjugate to form the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like enzyme to catalyze LC3 lipidation. The membrane targeting of the ATG12-ATG5-ATG16L1 complex is crucial for regulating autophagy and preventing ectopic membrane engagement. In this review, we summarize and discuss the potential mechanisms underlying ATG16L1 membrane recruitment, focusing on its intrinsic membrane-binding properties and partner-mediated recruitment pathways. We critically explore how these multiple mechanisms collectively ensure the proper localization and function of ATG16L1, thereby regulating the initiation of autophagy, LC3 lipidation, and the sequestration of bacteria during xenophagy.