Autophagy-independent role of ATG9A vesicles as carriers for galectin-9 secretion

Galectins play vital roles in cellular processes such as adhesion, communication, and survival, yet the mechanisms underlying their unconventional secretion remain poorly understood. This study identifies ATG9A, a core Autophagy protein, as a key regulator of Galectin-9 secretion via a mechanism independent of classical Autophagy, secretory Autophagy, or the LC3-dependent extracellular vesicle loading and secretion pathway. ATG9A vesicles function as specialized carriers, with the N-terminus of ATG9A and both carbohydrate recognition domains of Galectin-9 being critical for the process. TMED10 mediates the incorporation of Galectin-9 into ATG9A vesicles, which then fuse with the plasma membrane via the STX13-SNAP23-VAMP3 SNARE complex. Furthermore, ATG9A regulates the secretion of other proteins, including Galectin-4, Galectin-8, and annexin A6, but not IL-1β, Galectin-3, or FGF2. This mechanism is potentially conserved across other cell types, including monocytic cells, which underscores its broader significance in unconventional protein secretion.