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

Alexandra K. Davies, Daniel N. Itzhak, James R. Edgar, Tara L. Archuleta, Jennifer Hirst, Lauren P. Jackson, Margaret S. Robinson () and Georg H. H. Borner ()
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Alexandra K. Davies: University of Cambridge
Daniel N. Itzhak: Max Planck Institute of Biochemistry
James R. Edgar: University of Cambridge
Tara L. Archuleta: Vanderbilt University
Jennifer Hirst: University of Cambridge
Lauren P. Jackson: Vanderbilt University
Margaret S. Robinson: University of Cambridge
Georg H. H. Borner: Max Planck Institute of Biochemistry

Nature Communications, 2018, vol. 9, issue 1, 1-21

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06172-7

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