Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine
| Autor: | Anne Simonsen, Andrea F. Lopez-Clavijo, Alf Håkon Lystad, Joanne Durgan, David Oxley, Sven R. Carlsson, Judith Webster, Rupert Beale, Oliver Florey, Elena Marcassa, Michael A Wilson, Michael J.O. Wakelam, Rachel Ulferts, Katherine Sloan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cell- och molekylärbiologi Autophagy-Related Proteins Lipid-anchored protein chemistry.chemical_compound Mice 0302 clinical medicine ATG16L1 non-canonical autophagy 0303 health sciences Phosphatidylserine LC3-associated phagocytosis Cell biology Cysteine Endopeptidases Non canonical Influenza A virus ATG4 Female Macrolides ATG8 Microtubule-Associated Proteins Intracellular Signal Transduction phosphatidylserine Phagocytosis Phosphatidylserines Biology 03 medical and health sciences Immunity Autophagy Animals Humans Monensin Molecular Biology 030304 developmental biology Adaptor Proteins Signal Transducing Phosphatidylethanolamine Phosphatidylethanolamines Autophagosomes Cell Biology Autophagy-Related Protein 8 Family HCT116 Cells HEK293 Cells RAW 264.7 Cells chemistry Protein Processing Post-Translational 030217 neurology & neurosurgery Cell and Molecular Biology HeLa Cells |
| Zdroj: | Molecular cell. 81(9) |
| ISSN: | 1097-4164 1097-2765 |
| Popis: | Autophagy is a fundamental catabolic process essential for development, homeostasis and proper immune function 1. During autophagy, a cascade of ATG proteins target intracellular cargoes for lysosomal degradation and recycling 2. This pathway utilises a unique post-translational modification, the conjugation of ATG8 proteins to phosphatidylethanolamine (PE) at autophagosomes, which modulates cargo selection and maturation. ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway involving Single Membrane ATG8 Conjugation (SMAC) to endolysosomal compartments, which plays a key role in phagocytosis and other processes 3. It has been widely assumed that SMAC involves the same lipidation of ATG8 to PE, but this has yet to be formally tested. Here, we show that ATG8 undergoes alternative lipidation to phosphatidylserine (PS) during non-canonical autophagy/SMAC. Using mass spectrometry, we find that activation of SMAC, by pharmacological agents 4,5, or during non-canonical autophagy processes such as LC3-associated phagocytosis 6,7 and Influenza A virus infection 8, induces the covalent conjugation of ATG8 to PS, as well as PE. This alternative lipidation event is dependent on the ATG16L1 WD40 domain, and occurs at PS enriched endolysosomal membranes. Importantly, we find that the ATG8-PS and ATG8-PE adducts are differentially delipidated by isoforms of the ATG4 family, indicating significant molecular distinctions and mechanisms between these two species.Together, these results provide an important new insight into autophagy signalling, revealing an alternative form of the hallmark ATG8-lipidation event, so widely used to define and assay autophagy. Furthermore, ATG8-PS lipidation provides a specific ‘molecular signature’ for non-canonical autophagy, uncovering a novel means of detecting and monitoring this emerging pathway. |
| Databáze: | OpenAIRE |
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