ATG9 and ATG2 as lipid managers at the crossroads of autophagy and extracellular vesicle secretion

Macroautophagy/autophagy maintains cellular homeostasis by delivering cytoplasmic cargo to lysosomes for degradation. Autophagosome formation requires a substantial supply of phospholipids, mainly supported by the lipid scramblase ATG9A and lipid-transfer proteins ATG2A and ATG2B. Our recent study shows that loss of these proteins also alters small extracellular vesicle (sEV) secretion and composition. Cells lacking ATG9A or ATG2A/B release more sEVs during lysosomal inhibition, yet these vesicles contain less microtubule-associated protein 1A/1B-light chain 3 (LC3) and canonical autophagy cargo receptors. These changes are accompanied by impaired amphisome formation and extensive remodeling of the cellular lipidome. Our findings suggest that ATG9A and ATG2A/B coordinate membrane and cargo distribution between autophagy and endosomal secretion, raising the possibility that disrupted lipid supply to autophagosomes redirects lipids toward extracellular vesicle (EV) biogenesis.