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      ATG2 transports lipids to promote autophagosome biogenesis

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          Abstract

          During macroautophagic stress, autophagosomes can be produced continuously and in high numbers. Many different organelles have been reported as potential donor membranes for this sustained autophagosome growth, but specific machinery to support the delivery of lipid to the growing autophagosome membrane has remained unknown. Here we show that the autophagy protein, ATG2, without a clear function since its discovery over 20 yr ago, is in fact a lipid-transfer protein likely operating at the ER–autophagosome interface. ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro. An N-terminal fragment of ATG2A that supports lipid transfer in vitro is both necessary and fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells, implying that regulation of lipid homeostasis is the major autophagy-dependent activity of this protein and, by extension, that protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation.

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          Most cited references28

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          Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

          Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.
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            VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites

            Structural and biochemical studies show that VPS13 family proteins are lipid transporters. VPS13A and VPS13C tether the ER to mitochondria and to endosomes/lysosomes, respectively, suggesting lipid dyshomeostasis as the cause of chorea acanthocytosis and Parkinson’s disease resulting from their mutations.
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              • Record: found
              • Abstract: not found
              • Article: not found

              Isolation and characterization of autophagy-defective mutants ofSaccharomyces cerevisiae

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                Author and article information

                Journal
                The Journal of Cell Biology
                J. Cell Biol.
                Rockefeller University Press
                0021-9525
                1540-8140
                April 05 2019
                : jcb.201811139
                Affiliations
                [1 ]Department of Cell Biology, Yale University School of Medicine, New Haven, CT
                [2 ]Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY
                Article
                10.1083/jcb.201811139
                7441e6ec-04dc-45b4-981b-5a0873c9c888
                © 2019

                Free to read

                http://www.rupress.org/terms/

                https://creativecommons.org/licenses/by-nc-sa/4.0/

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