ATG9A facilitates the closure of mammalian autophagosomes
Ruheena Javed, Muriel Mari, Einar S Trosdal, Thabata Duque, Masroor Ahmad Paddar, Lee Allers, Michal Mudd, Aurore Claude‐Taupin, Prithvi Reddy Akepati, Emily Hendrix, Yi He, Michelle Salemi, Brett S. Phinney, Yasuo Uchiyama, Fulvio Reggiori, Vojo Deretić
Abstract
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.