A conserved ATG2-GABARAP family interaction is critical for phagophore formation

Mihaela Bozic, Luuk van den Bekerom, Beth A Milne, Nicola Goodman, Lisa Roberston, Alan Prescott, Thomas Macartney, Nina Dawe, David McEwan

Research output: Contribution to journalArticle

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Abstract

The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore elongation and closure, but little mechanistic detail is known about their function. 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 ATG2A-GABARAP interaction mutants are unable to form and close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double-knockout cells. In contrast, the ATG2A-WIPI4 interaction mutant fully restored phagophore formation and autophagy flux, similar to wild-type ATG2A. Taken together, we provide new mechanistic insights into the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP/GABARAP-L1 interaction is essential for phagophore formation, whereas ATG2-WIPI4 interaction is dispensable.

Original languageEnglish
Article numbere48412
Pages (from-to)1-17
Number of pages17
JournalEMBO Reports
Early online date3 Feb 2020
DOIs
Publication statusPublished - 3 Feb 2020

Fingerprint

Autophagy
Elongation
Seals
Recycling
Proteins
Fluxes
Degradation
Homeostasis
human ATG2B protein

Keywords

  • Autophagy
  • phagophore
  • autophagosome
  • GABARAP
  • ATG2
  • autophagy

Cite this

Bozic, Mihaela ; van den Bekerom, Luuk ; Milne, Beth A ; Goodman, Nicola ; Roberston, Lisa ; Prescott, Alan ; Macartney, Thomas ; Dawe, Nina ; McEwan, David. / A conserved ATG2-GABARAP family interaction is critical for phagophore formation. In: EMBO Reports. 2020 ; pp. 1-17.
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abstract = "The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore elongation and closure, but little mechanistic detail is known about their function. 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 ATG2A-GABARAP interaction mutants are unable to form and close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double-knockout cells. In contrast, the ATG2A-WIPI4 interaction mutant fully restored phagophore formation and autophagy flux, similar to wild-type ATG2A. Taken together, we provide new mechanistic insights into the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP/GABARAP-L1 interaction is essential for phagophore formation, whereas ATG2-WIPI4 interaction is dispensable.",
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Bozic, M, van den Bekerom, L, Milne, BA, Goodman, N, Roberston, L, Prescott, A, Macartney, T, Dawe, N & McEwan, D 2020, 'A conserved ATG2-GABARAP family interaction is critical for phagophore formation', EMBO Reports, pp. 1-17. https://doi.org/10.15252/embr.201948412

A conserved ATG2-GABARAP family interaction is critical for phagophore formation. / Bozic, Mihaela ; van den Bekerom, Luuk ; Milne, Beth A; Goodman, Nicola ; Roberston, Lisa ; Prescott, Alan; Macartney, Thomas; Dawe, Nina ; McEwan, David.

In: EMBO Reports, 03.02.2020, p. 1-17.

Research output: Contribution to journalArticle

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AU - Bozic, Mihaela

AU - van den Bekerom, Luuk

AU - Milne, Beth A

AU - Goodman, Nicola

AU - Roberston, Lisa

AU - Prescott, Alan

AU - Macartney, Thomas

AU - Dawe, Nina

AU - McEwan, David

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N2 - The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore elongation and closure, but little mechanistic detail is known about their function. 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 ATG2A-GABARAP interaction mutants are unable to form and close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double-knockout cells. In contrast, the ATG2A-WIPI4 interaction mutant fully restored phagophore formation and autophagy flux, similar to wild-type ATG2A. Taken together, we provide new mechanistic insights into the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP/GABARAP-L1 interaction is essential for phagophore formation, whereas ATG2-WIPI4 interaction is dispensable.

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KW - autophagosome

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Bozic M, van den Bekerom L, Milne BA, Goodman N, Roberston L, Prescott A et al. A conserved ATG2-GABARAP family interaction is critical for phagophore formation. EMBO Reports. 2020 Feb 3;1-17. e48412. https://doi.org/10.15252/embr.201948412