Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex.
Saikat ChowdhuryChinatsu OtomoAlexander LeitnerKazuto OhashiRuedi AebersoldGabriel C LanderTakanori OtomoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
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.
Keyphrases
- endoplasmic reticulum
- estrogen receptor
- mass spectrometry
- breast cancer cells
- cell death
- signaling pathway
- electron microscopy
- endoplasmic reticulum stress
- endothelial cells
- small molecule
- regulatory t cells
- immune response
- big data
- electronic health record
- high resolution
- protein protein
- fatty acid
- deep learning
- machine learning
- amino acid
- tandem mass spectrometry
- gas chromatography
- pluripotent stem cells