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

  • Nat Commun. 2025 May 7;16(1):4259. doi: 10.1038/s41467-025-59605-5.
Wenting Zhang  #  1 ,  Cuicui Ji  #  1 ,  Xianghua Li  #  1 ,  Tianlong He  #  1 ,  Wei Jiang  1 ,  Yukun Liu  1 ,  Meiling Wu  1 ,  Yunpeng Zhao  1 ,  Xuechai Chen  1 ,  Xiaoli Wang  1 ,  Jian Li  2 ,  Haolin Zhang  3 ,  Juan Wang  4
Affiliations
  • 1. College of Chemistry and Life Science, Beijing University of Technology, Beijing, China.
  • 2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 3. College of Chemistry and Life Science, Beijing University of Technology, Beijing, China. [email protected].
  • 4. College of Chemistry and Life Science, Beijing University of Technology, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 40335523 DOI: 10.1038/s41467-025-59605-5
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.

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