Xu Peiqi, Zhang Ting, Yu Fangfang, Guo Lixia, Yang Yanan
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
Biochem Biophys Res Commun. 2025 Feb 2;747:151254. doi: 10.1016/j.bbrc.2024.151254. Epub 2024 Dec 27.
The autophagosome is a double-membrane organelle that executes macroautophagy. Previous studies have shown that the autophagosome formation is driven by autophagy-related genes, among which ATG9 is the only conserved transmembrane protein and has been shown to play a critical role in the autophagosome formation. However, how ATG9 binds to the growing autophagosome membrane has remained uncertain. Herein, we report that ATG9 binds to LC3, an essential membrane component of the autophagosome, thereby allowing ATG9 to incorporate into the autophagosome membrane. Mechanistically, we show that ATG9 interacts with LC3 through its UIM motives, which bind to the UDS site of LC3. Interrupting such UIM-UDS interaction abolishes the autophagosome association of ATG9 and suppresses the autophagosome formation. Collectively, our findings reveal a novel mechanism regulating autophagosome biogenesis and suggest that the interaction of ATG9 with LC3 is critical for ATG9 binding to the growing autophagosome membrane.
自噬体是一种执行巨自噬的双膜细胞器。先前的研究表明，自噬体的形成由自噬相关基因驱动，其中ATG9是唯一保守的跨膜蛋白，并且已被证明在自噬体形成中起关键作用。然而，ATG9如何与正在生长的自噬体膜结合仍不确定。在此，我们报告ATG9与LC3结合，LC3是自噬体的一种重要膜成分，从而使ATG9能够整合到自噬体膜中。从机制上讲，我们表明ATG9通过其UIM基序与LC3相互作用，该基序与LC3的UDS位点结合。中断这种UIM-UDS相互作用会消除ATG9与自噬体的关联并抑制自噬体的形成。总体而言，我们的研究结果揭示了一种调节自噬体生物发生的新机制，并表明ATG9与LC3的相互作用对于ATG9结合到正在生长的自噬体膜至关重要。
