AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A.
Archuleta, Tara L
Springer Science and Business Media LLC
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Davies, A., Itzhak, D. N., Edgar, J., Archuleta, T. L., Hirst, J., Jackson, L. P., Robinson, M., & et al. (2018). AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A.. Nat Commun, 9 (1), 3958. https://doi.org/10.1038/s41467-018-06172-7
Adaptor protein 4 (AP-4) is an ancient membrane trafficking complex, whose function has largely remained elusive. In humans, AP-4 deficiency causes a severe neurological disorder of unknown aetiology. We apply unbiased proteomic methods, including 'Dynamic Organellar Maps', to find proteins whose subcellular localisation depends on AP-4. We identify three transmembrane cargo proteins, ATG9A, SERINC1 and SERINC3, and two AP-4 accessory proteins, RUSC1 and RUSC2. We demonstrate that AP-4 deficiency causes missorting of ATG9A in diverse cell types, including patient-derived cells, as well as dysregulation of autophagy. RUSC2 facilitates the transport of AP-4-derived, ATG9A-positive vesicles from the trans-Golgi network to the cell periphery. These vesicles cluster in close association with autophagosomes, suggesting they are the "ATG9A reservoir" required for autophagosome biogenesis. Our study uncovers ATG9A trafficking as a ubiquitous function of the AP-4 pathway. Furthermore, it provides a potential molecular pathomechanism of AP-4 deficiency, through dysregulated spatial control of autophagy.
Hela Cells, Microtubules, Phagosomes, Transport Vesicles, trans-Golgi Network, Humans, Adaptor Proteins, Signal Transducing, Carrier Proteins, Membrane Proteins, Vesicular Transport Proteins, Adaptor Protein Complex 4, Proteomics, Protein Binding, Phenotype, Models, Biological, Autophagy, Autophagy-Related Proteins
Wellcome Trust (086598/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
External DOI: https://doi.org/10.1038/s41467-018-06172-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286934
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/