AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A.
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Authors
Archuleta, Tara L
Hirst, Jennifer
Robinson, Margaret S
Publication Date
2018-09-27Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
9
Issue
1
Pages
3958
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Davies, A. K., Itzhak, D. N., Edgar, J. R., Archuleta, T. L., Hirst, J., Jackson, L. P., Robinson, M. S., & 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
Abstract
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.
Keywords
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
Sponsorship
Wellcome Trust (086598/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-06172-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286934
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