Scilight Press

Autophagy-related proteins are increasingly recognized for functions beyond canonical autophagosome-mediated degradation. Our recent work identifies ATG9A-positive vesicles as a dedicated, autophagy-independent pathway for selective unconventional protein secretion (UcPS). This route is essential for the extracellular release of tandem-repeat galectins, including galectin-9, galectin-4 and galectin-8, but is dispensable for other UcPS cargos such as IL-1β, galectin-3 or FGF2. Mechanistically, galectins are physically enclosed within ATG9A vesicles in a TMED10-dependent manner. ATG9A vesicles traffic from the Golgi via an AP-4–RUSC2 module and fuse with the plasma membrane through a STX13–SNAP23–VAMP3 SNARE complex. This pathway is mechanistically distinct from secretory autophagy, exosome release and LC3-dependent extracellular vesicle secretion. Together, these findings establish ATG9A vesicles as selective carriers in UcPS and expand the functional landscape of ATG proteins beyond degradation.