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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Protein Complex 4
  • Adaptor Proteins, Signal Transducing
  • Atg9a protein, human
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Membrane Proteins
  • RUSC1 protein, human
  • RUSC2 protein, human
  • SERINC1 protein, human
  • Vesicular Transport Proteins