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  • Faa1 membrane binding drives positive feedback in autophagosome biogenesis via fatty acid activation.

Faa1 membrane binding drives positive feedback in autophagosome biogenesis via fatty acid activation.

The Journal of cell biology (2024-04-04)
Verena Baumann, Sonja Achleitner, Susanna Tulli, Martina Schuschnig, Lara Klune, Sascha Martens
ABSTRACT

Autophagy serves as a stress response pathway by mediating the degradation of cellular material within lysosomes. In autophagy, this material is encapsulated in double-membrane vesicles termed autophagosomes, which form from precursors referred to as phagophores. Phagophores grow by lipid influx from the endoplasmic reticulum into Atg9-positive compartments and local lipid synthesis provides lipids for their expansion. How phagophore nucleation and expansion are coordinated with lipid synthesis is unclear. Here, we show that Faa1, an enzyme activating fatty acids, is recruited to Atg9 vesicles by directly binding to negatively charged membranes with a preference for phosphoinositides such as PI3P and PI4P. We define the membrane-binding surface of Faa1 and show that its direct interaction with the membrane is required for its recruitment to phagophores. Furthermore, the physiological localization of Faa1 is key for its efficient catalysis and promotes phagophore expansion. Our results suggest a positive feedback loop coupling phagophore nucleation and expansion to lipid synthesis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cerulenin, Cephalosporium caerulens, An antifungal antibiotic that inhibits sterol and fatty acid biosynthesis.
Sigma-Aldrich
Rapamycin, ≥95% (HPLC), powder
Sigma-Aldrich
Protease Inhibitor Cocktail, for use in purification of Histidine-tagged proteins, DMSO solution