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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Davies, Alexandra K  ORCID logo  https://orcid.org/0000-0002-1594-8780
Archuleta, Tara L 
Hirst, Jennifer 

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.

Description

Keywords

Adaptor Protein Complex 4, Adaptor Proteins, Signal Transducing, Autophagy, Autophagy-Related Proteins, Carrier Proteins, HeLa Cells, Humans, Membrane Proteins, Microtubules, Models, Biological, Phagosomes, Phenotype, Protein Binding, Proteomics, Transport Vesicles, Vesicular Transport Proteins, trans-Golgi Network

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (086598/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)