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  AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A

Davies, A. K., Itzhak, D. N., Edgar, J. R., Archuleta, T. L., Hirst, J., Jackson, L. P., et al. (2018). AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nature Communications, 9: 3958. doi:10.1038/s41467-018-06172-7.

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 Creators:
Davies, Alexandra K.1, Author
Itzhak, Daniel N.2, Author              
Edgar, James R.1, Author
Archuleta, Tara L.1, Author
Hirst, Jennifer1, Author
Jackson, Lauren P.1, Author
Robinson, Margaret S.1, Author
Borner, Georg H. H.3, Author              
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Borner, Georg / Systems Biology of Membrane Trafficking, Max Planck Institute of Biochemistry, Max Planck Society, ou_3060205              

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Free keywords: PROGRESSIVE SPASTIC PARAPLEGIA; PROTEIN COMPLEX-4 AP-4; INTELLECTUAL DISABILITY; PRIMARY NEURONS; ACCESSORY PROTEIN; DEFICIENCY CAUSES; LIPID-SYNTHESIS; ADAPTER; SPECIFICITY; PROTEOMICSScience & Technology - Other Topics;
 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.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Published online
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 9 Sequence Number: 3958 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723