Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex
- PMID: 30185561
- PMCID: PMC6196511
- DOI: 10.1073/pnas.1811874115
Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex
Abstract
Autophagy is an enigmatic cellular process in which double-membrane compartments, called "autophagosomes, form de novo adjacent to the endoplasmic reticulum (ER) and package cytoplasmic contents for delivery to lysosomes. Expansion of the precursor membrane phagophore requires autophagy-related 2 (ATG2), which localizes to the PI3P-enriched ER-phagophore junction. We combined single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical analyses to characterize human ATG2A in complex with the PI3P effector WIPI4. ATG2A is a rod-shaped protein that can bridge neighboring vesicles through interactions at each of its tips. WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle. These data suggest that the ATG2A-WIPI4 complex mediates ER-phagophore association and/or tethers vesicles to the ER-phagophore junction, establishing the required organization for phagophore expansion via the transfer of lipid membranes from the ER and/or the vesicles to the phagophore.
Keywords: ATG2; autophagy; chemical cross-linking coupled with mass spectrometry; membrane tethering; single-particle analysis.
Conflict of interest statement
The authors declare no conflict of interest.
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Comment in
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Membrane tethering by the autophagy ATG2A-WIPI4 complex.Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10540-10541. doi: 10.1073/pnas.1814759115. Epub 2018 Oct 1. Proc Natl Acad Sci U S A. 2018. PMID: 30275332 Free PMC article. No abstract available.
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