Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs



: Javed Ruheena, Jain Ashish, Duque Thabata, Hendrix Emily, Paddar Masroor Ahmad, Khan Sajjad, Claude-Taupin Aurore, Jia Jingyue, Allers Lee, Wang Fulong, Mudd Michal, Timmins Graham, Lidke Keith, Rusten Tor Erik, Akepati Prithvi Reddy, He Yi, Reggiori Fulvio, Eskelinen Eeva-Liisa, Deretic Vojo

Publisher: EMBO Press

: 2023

: EMBO Journal

: The EMBO journal

: EMBO J

: e112845

: 42

: 14

: 0261-4189

: 1460-2075

DOI: https://doi.org/10.15252/embj.2022112845

: https://doi.org/10.15252/embj.2022112845

: https://research.utu.fi/converis/portal/detail/Publication/179710262


The canonical autophagy pathway in mammalian cells sequesters diverse cytoplasmic cargo within the double membrane autophagosomes that eventually convert into degradative compartments via fusion with endolysosomal intermediates. Here, we report that autophagosomal membranes show permeability in cells lacking principal ATG8 proteins (mATG8s) and are unable to mature into autolysosomes. Using a combination of methods including a novel in vitro assay to measure membrane sealing, we uncovered a previously unappreciated function of mATG8s to maintain autophagosomal membranes in a sealed state. The mATG8 proteins GABARAP and LC3A bind to key ESCRT-I components contributing, along with other ESCRTs, to the integrity and imperviousness of autophagic membranes. Autophagic organelles in cells lacking mATG8s are permeant, are arrested as amphisomes, and do not progress to functional autolysosomes. Thus, autophagosomal organelles need to be maintained in a sealed state in order to become lytic autolysosomes.

Last updated on 2025-27-03 at 21:50