ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system
| Autor: | Susanne Zellner, Grace Khuu, Louise Uoselis, Benjamin S. Padman, Runa S.J. Lindblom, Marvin Skulsuppaisarn, Thanh Ngoc Nguyen, Michael Lazarou, Emily M. Watts, Wai Kit Lam, Christian Behrends |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Autophagosome
Proteases GABARAP Autophagosome maturation ATG8 Ubiquitin-Protein Ligases Vesicular Transport Proteins Autophagy-Related Proteins Biology Parkin 03 medical and health sciences 0302 clinical medicine Imaging Three-Dimensional Microscopy Electron Transmission Artificial Intelligence Mitophagy Humans Molecular Biology 030304 developmental biology Adaptor Proteins Signal Transducing 0303 health sciences Autophagy Autophagosomes Membrane Proteins Cell Biology Autophagy-Related Protein 8 Family Lipid Metabolism Cell biology Mitochondria Cysteine Endopeptidases Protein Transport HEK293 Cells Apoptosis Regulatory Proteins Microtubule-Associated Proteins Protein Kinases 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | Molecular cell. 81(9) |
| ISSN: | 1097-4164 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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