ATG9A facilitates the closure of mammalian autophagosomes

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.