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

  • Nat Commun. 2018 Sep 27;9(1):3958. doi: 10.1038/s41467-018-06172-7.
Alexandra K Davies  1 ,  Daniel N Itzhak  2 ,  James R Edgar  1 ,  Tara L Archuleta  3  4 ,  Jennifer Hirst  1 ,  Lauren P Jackson  3  4 ,  Margaret S Robinson  5 ,  Georg H H Borner  6
Affiliations
  • 1. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
  • 2. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
  • 3. Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
  • 4. Center for Structural Biology, Vanderbilt University, Nashville, TN, 37235, USA.
  • 5. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. [email protected].
  • 6. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany. [email protected].
PMID: 30262884 DOI: 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.