ATG9 Not Just an Autophagy Related Protein

Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as “non-canonical functions”, and summarise the broader role of ATG9A in cell homeostasis.