ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system

Thanh Ngoc, Nguyen; Padman, Benjamin Scott; Zellner, Susanne; Khuu, Grace; Uoselis, Louise; Lam, Wai Kit; Skulsuppaisarn, Marvin; Lindblom, Runa S. J.; Watts, Emily M.; Behrends, Christian and Lazarou, Michael (2021): ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system. In: Molecular Cell, Vol. 81, No. 9: 2013-

Abstract

The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Munich Cluster for Systems Neurology (SyNergy)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1097-2765
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198