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AP-4 vesicles unmasked by organellar proteomics to reveal their cargo and machinery

Alexandra K. Davies, Daniel N. Itzhak, James R. Edgar, Tara L. Archuleta, Jennifer Hirst, Lauren P. Jackson, Margaret S. Robinson, Georg H. H. Borner
doi: https://doi.org/10.1101/235226
Alexandra K. Davies
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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Daniel N. Itzhak
2Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany
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James R. Edgar
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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Tara L. Archuleta
3Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA
4Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA
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Jennifer Hirst
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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Lauren P. Jackson
3Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA
4Center for Structural Biology, Vanderbilt University, Nashville, TN 37235, USA
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Margaret S. Robinson
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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  • For correspondence: borner@biochem.mpg.de msr12@cam.ac.uk
Georg H. H. Borner
2Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany
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  • For correspondence: borner@biochem.mpg.de msr12@cam.ac.uk
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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 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.

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Posted December 18, 2017.
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AP-4 vesicles unmasked by organellar proteomics to reveal their cargo and machinery
Alexandra K. Davies, Daniel N. Itzhak, James R. Edgar, Tara L. Archuleta, Jennifer Hirst, Lauren P. Jackson, Margaret S. Robinson, Georg H. H. Borner
bioRxiv 235226; doi: https://doi.org/10.1101/235226
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AP-4 vesicles unmasked by organellar proteomics to reveal their cargo and machinery
Alexandra K. Davies, Daniel N. Itzhak, James R. Edgar, Tara L. Archuleta, Jennifer Hirst, Lauren P. Jackson, Margaret S. Robinson, Georg H. H. Borner
bioRxiv 235226; doi: https://doi.org/10.1101/235226

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