Abstract
An enigmatic step in de novo formation of the autophagosome membrane compartment is the expansion of the precursor membrane phagophore, which requires the acquisition of lipids to serve as building blocks. Autophagy-related 2 (ATG2), the rod-shaped protein that tethers phosphatidylinositol 3-phosphate (PI3P)-enriched phagophores to the endoplasmic reticulum (ER), is suggested to be essential for phagophore expansion, but the underlying mechanism remains unclear. Here, we demonstrate that human ATG2A is a lipid transfer protein. ATG2A can extract lipids from membrane vesicles and unload them to other vesicles. Lipid transfer by ATG2A is more efficient between tethered vesicles than between untethered vesicles. The PI3P effectors WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles, thereby facilitating ATG2A-mediated tethering and lipid transfer between PI3P-containing vesicles and PI3P-free vesicles. Based on these results, we propose that ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion.
Highlights
Autophagy is the bulk degradation-recycling process that plays crucial roles in the maintenance of cellular homeostasis in eukaryotes (Choi, Ryter, & Levine, 2013; Levine & Kroemer, 2019; Mizushima & Komatsu, 2011; Reggiori & Klionsky, 2013)
endoplasmic reticulum (ER) anchoring by the N tip was demonstrated by Kotani et al, who created an autophagy-deficient Atg2 mutant by deleting the N-terminal 21 residues and restored autophagic activity by genetically fusing the transmembrane domain of the ER resident Sec71 protein to the N-terminus of the mutant (Kotani et al, 2018)
WIPI4 has been shown to localize to the “omegasome” (Lu et al, 2011), the phosphatidylinositol 3-phosphate (PI3P)-positive transient region between the ER and the phagophore (Axe et al, 2008)
Summary
Autophagy is the bulk degradation-recycling process that plays crucial roles in the maintenance of cellular homeostasis in eukaryotes (Choi, Ryter, & Levine, 2013; Levine & Kroemer, 2019; Mizushima & Komatsu, 2011; Reggiori & Klionsky, 2013). The edge of the cup-shaped phagophore is associated with the ER (Hayashi-Nishino et al, 2009; Uemura et al, 2014; Yla-Anttila, Vihinen, Jokitalo, & Eskelinen, 2009), and this association is maintained during phagophore expansion (Graef, Friedman, Graham, Babu, & Nunnari, 2013; Suzuki, Akioka, Kondo-Kakuta, Yamamoto, & Ohsumi, 2013). This intimate spatial relationship has led to the hypothesis that the ER feeds the phagophore with lipids, enabling phagophore expansion (Tooze & Yoshimori, 2010). The mechanism through which these proteins enable membrane expansion remains unknown (Mizushima, 2018)
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