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A conserved ATG2-GABARAP interaction is critical for phagophore closure

Mihaela Bozic, Luuk van den Bekerom, Beth A. Milne, Nicola Goodman, Lisa Roberston, Alan R. Prescott, Thomas J. Macartney, Nina Dawe, View ORCID ProfileDavid G. McEwan
doi: https://doi.org/10.1101/624627
Mihaela Bozic
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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Luuk van den Bekerom
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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Beth A. Milne
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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Nicola Goodman
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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Lisa Roberston
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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Alan R. Prescott
2Dundee Imaging Facility, School of Life Sciences, University of Dundee, Dundee, UK.
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Thomas J. Macartney
3MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
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Nina Dawe
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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David G. McEwan
1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
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  • ORCID record for David G. McEwan
  • For correspondence: d.g.mcewan@dundee.ac.uk
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Abstract

The intracellular trafficking pathway, macroautophagy, acts as a recycling and disposal service that can be upregulated during periods of stress, to maintain cellular homeostasis. An essential transition point in the pathway is the sealing of the immature phagophore to form an autophagosome, isolating unwanted cargo prior to lysosomal degradation. However, little mechanistic detail is known about phagophore closure. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore closure. We have identified a highly-conserved motif driving the interaction between human ATG2 and GABARAP proteins that is in close proximity to the ATG2-WIPI4 interaction site. We show that the ATG2-GABARAP interaction mutants are unable to close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double knock-out cells. In contrast, the ATG2-WIPI4 interaction mutant fully restored phagophore closure and autophagy flux, similar to wild type ATG2. Taken together, we provide new mechanistic insights to the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP interaction is essential for phagophore closure, whereas ATG2-WIPI4 interaction is dispensable.

  • Abbreviations

    ATG2
    Autophagy-related protein 2
    ESCRT
    endosomal sorting complex required for transport
    GABARAP
    Gamma-aminobutyric acid receptor-associated protein
    GIM
    GABARAP Interaction Motif
    GST
    Glutathione S-transferase
    LIR
    LC3 interaction region
    MAP1LC3 (LC3)
    Microtubule-associated proteins 1A/1B light chain
    PtIns3P
    phosphatidylinositol-3-phosphate
    PI3K
    PtsIns3P kinase
    SQSTM1
    Sequestosome-1
    VPS34
    Vacuolar Protein sorting 34
    WIPI
    WD repeat domain phosphoinositide-interacting protein
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted May 03, 2019.
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    A conserved ATG2-GABARAP interaction is critical for phagophore closure
    Mihaela Bozic, Luuk van den Bekerom, Beth A. Milne, Nicola Goodman, Lisa Roberston, Alan R. Prescott, Thomas J. Macartney, Nina Dawe, David G. McEwan
    bioRxiv 624627; doi: https://doi.org/10.1101/624627
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    A conserved ATG2-GABARAP interaction is critical for phagophore closure
    Mihaela Bozic, Luuk van den Bekerom, Beth A. Milne, Nicola Goodman, Lisa Roberston, Alan R. Prescott, Thomas J. Macartney, Nina Dawe, David G. McEwan
    bioRxiv 624627; doi: https://doi.org/10.1101/624627

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