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

Wenting Zhang, Cuicui Ji, Xianghua Li, Tianlong He, Wei Jiang, Yukun Liu, Meiling Wu, Yunpeng Zhao, Xuechai Chen, Xiaoli Wang, Jian Li, Haolin Zhang () and Juan Wang ()
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Wenting Zhang: Beijing University of Technology
Cuicui Ji: Beijing University of Technology
Xianghua Li: Beijing University of Technology
Tianlong He: Beijing University of Technology
Wei Jiang: Beijing University of Technology
Yukun Liu: Beijing University of Technology
Meiling Wu: Beijing University of Technology
Yunpeng Zhao: Beijing University of Technology
Xuechai Chen: Beijing University of Technology
Xiaoli Wang: Beijing University of Technology
Jian Li: Shandong University
Haolin Zhang: Beijing University of Technology
Juan Wang: Beijing University of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59605-5

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