RT Journal Article
SR Electronic
T1 AP-4 vesicles unmasked by organellar proteomics to reveal their cargo and machinery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 235226
DO 10.1101/235226
A1 Alexandra K. Davies
A1 Daniel N. Itzhak
A1 James R. Edgar
A1 Tara L. Archuleta
A1 Jennifer Hirst
A1 Lauren P. Jackson
A1 Margaret S. Robinson
A1 Georg H. H. Borner
YR 2017
UL http://biorxiv.org/content/early/2017/12/18/235226.abstract
AB 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 multiple unbiased proteomic methods, including ‘Dynamic Organellar Maps’, to find proteins whose subcellular localisation depends on AP-4. We identify three highly conserved 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 neuroblastoma and AP-4 patient-derived cells, as well as dysregulation of autophagy. Furthermore, we show that RUSC2 facilitates the microtubule plus-end-directed transport of AP-4-derived, ATG9A-positive vesicles from the TGN to the cell periphery. Since ATG9A has essential functions in neuronal homeostasis, our data not only uncover the ubiquitous function of the AP-4 pathway, but also begin to explain the molecular pathomechanism of AP-4 deficiency.