ATG9A facilitates the closure of mammalian autophagosomes

J Cell Biol. 2025 Feb 3;224(2):e202404047. doi: 10.1083/jcb.202404047. Epub 2025 Jan 2.

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.

MeSH terms

  • Animals
  • Autophagosomes* / metabolism
  • Autophagy*
  • Autophagy-Related Proteins* / genetics
  • Autophagy-Related Proteins* / metabolism
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Vesicular Transport Proteins* / genetics
  • Vesicular Transport Proteins* / metabolism

Substances

  • Autophagy-Related Proteins
  • ATG9A protein, human
  • Membrane Proteins
  • Vesicular Transport Proteins
  • Endosomal Sorting Complexes Required for Transport