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

Author

Listed:
  • 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
    Vanderbilt University)

  • Jennifer Hirst

    (University of Cambridge)

  • Lauren P. Jackson

    (Vanderbilt University
    Vanderbilt University)

  • Margaret S. Robinson

    (University of Cambridge)

  • Georg H. H. Borner

    (Max Planck Institute of Biochemistry)

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.

Suggested Citation

  • Alexandra K. Davies & Daniel N. Itzhak & James R. Edgar & Tara L. Archuleta & Jennifer Hirst & Lauren P. Jackson & Margaret S. Robinson & Georg H. H. Borner, 2018. "AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A," Nature Communications, Nature, vol. 9(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06172-7
    DOI: 10.1038/s41467-018-06172-7
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    Cited by:

    1. Julia P. Schessner & Vincent Albrecht & Alexandra K. Davies & Pavel Sinitcyn & Georg H. H. Borner, 2023. "Deep and fast label-free Dynamic Organellar Mapping," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Afshin Saffari & Barbara Brechmann & Cedric Böger & Wardiya Afshar Saber & Hellen Jumo & Dosh Whye & Delaney Wood & Lara Wahlster & Julian E. Alecu & Marvin Ziegler & Marlene Scheffold & Kellen Winden, 2024. "High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Elodie Mailler & Carlos M. Guardia & Xiaofei Bai & Michal Jarnik & Chad D. Williamson & Yan Li & Nunziata Maio & Andy Golden & Juan S. Bonifacino, 2021. "The autophagy protein ATG9A enables lipid mobilization from lipid droplets," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Oliver M. Crook & Colin T. R. Davies & Lisa M. Breckels & Josie A. Christopher & Laurent Gatto & Paul D. W. Kirk & Kathryn S. Lilley, 2022. "Inferring differential subcellular localisation in comparative spatial proteomics using BANDLE," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    5. Daehun Park & Yumei Wu & Xinbo Wang & Swetha Gowrishankar & Aaron Baublis & Pietro De Camilli, 2023. "Synaptic vesicle proteins and ATG9A self-organize in distinct vesicle phases within synapsin condensates," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Alexandra K. Davies & Julian E. Alecu & Marvin Ziegler & Catherine G. Vasilopoulou & Fabrizio Merciai & Hellen Jumo & Wardiya Afshar-Saber & Mustafa Sahin & Darius Ebrahimi-Fakhari & Georg H. H. Borne, 2022. "AP-4-mediated axonal transport controls endocannabinoid production in neurons," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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