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ATG2A engages Rab1a and ARFGAP1 positive membranes during autophagosome biogenesis
Devin M Fuller1,2, Yumei Wu1,2,3,4,5, Florian Schueder1,6
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT.
Biorxiv : the Preprint Server for Biology
|April 8, 2025
Summary
Autophagosome formation involves the lipid transporter ATG2A interacting with Rab1a on early secretory membranes. This interaction is crucial for autophagosome biogenesis, highlighting a novel connection in cellular waste removal.
Area of Science:
- Cell Biology
- Molecular Biology
- Autophagy Research
Background:
- Autophagosomes are essential for cellular homeostasis, but the origin of their membranes and the machinery involved remain unclear.
- The lipid transporter ATG2A plays a role in autophagosome expansion, yet its upstream regulation and membrane sourcing are poorly understood.
Purpose of the Study:
- To investigate the origins of autophagosome seed membranes and their connection to lipid transport machinery.
- To identify proteins interacting with ATG2A during autophagosome biogenesis and elucidate their function.
Main Methods:
- Proximity labeling techniques to identify interacting proteins.
- Advanced fluorescence microscopy to visualize protein localization and dynamics.
- siRNA-mediated gene depletion to assess protein function in autophagy.
Main Results:
- ATG2A localizes to extra-Golgi ARFGAP1 puncta during autophagosome formation.
- Rab1a, but not ARFGAP1, is essential for macroautophagy and interacts with ATG2A.
- Depletion of Rab1a phenocopies ATG2A depletion, blocking autophagy downstream of LC3B lipidation.
- Perturbations in autophagosome formation or the secretory pathway lead to the accumulation of ARFGAP1 and Rab1a with autophagic machinery.
Conclusions:
- ATG2A engages a Rab1a complex on specific early secretory membranes early in autophagosome biogenesis.
- This study reveals a novel mechanism linking early secretory pathways to autophagosome formation via the ATG2A-Rab1a interaction.
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