Javed Ruheena, Mari Muriel, Trosdal Einar, Duque Thabata, Paddar Masroor Ahmad, Allers Lee, Mudd Michal H, Claude-Taupin Aurore, Akepati Prithvi Reddy, Hendrix Emily, He Yi, Salemi Michelle, Phinney Brett, Uchiyama Yasuo, Reggiori Fulvio, Deretic Vojo
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center , Albuquerque, NM, USA.
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
J Cell Biol. 2025 Feb 3;224(2). doi: 10.1083/jcb.202404047. Epub 2025 Jan 2.
Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite for its subsequent fusion with endolysosomal organelles and degradation of the sequestered cargo. ATG9A, a key integral membrane protein of the autophagy pathway, is best known for its role in the formation and expansion of phagophores. Here, we report a hitherto unappreciated function of mammalian ATG9A in directing autophagosome closure. ATG9A partners with IQGAP1 and key ESCRT-III component CHMP2A to facilitate this final stage in autophagosome formation. Thus, ATG9A is a central hub governing all major aspects of autophagosome membrane biogenesis, from phagophore formation to its closure, and is a unique ATG factor with progressive functionalities affecting the physiological outputs of autophagy.
经典自噬在称为自噬体的特殊双膜细胞器内捕获一系列注定要被溶酶体降解的细胞质成分。当正在生长的吞噬泡经历依赖于内体分选转运复合体（ESCRT）的膜封闭时，自噬体即告完成，这是其随后与内溶酶体细胞器融合并降解所隔离货物的先决条件。ATG9A是自噬途径的一种关键整合膜蛋白，因其在吞噬泡形成和扩张中的作用而最为人所知。在此，我们报告了哺乳动物ATG9A在指导自噬体封闭方面迄今未被认识到的功能。ATG9A与IQGAP1和关键的ESCRT-III组分CHMP2A合作，以促进自噬体形成的这一最后阶段。因此，ATG9A是一个控制自噬体膜生物发生所有主要方面的中心枢纽，从吞噬泡形成到其封闭，并且是一个具有影响自噬生理输出的渐进性功能的独特自噬相关因子。
