• The phosphatidylinositol 3-phosphate-binding protein SNX4 controls ATG9A recycling and autophagy.

The phosphatidylinositol 3-phosphate-binding protein SNX4 controls ATG9A recycling and autophagy.

Journal of cell science (2021-01-21)
Anthony Ravussin, Andreas Brech, Sharon A Tooze, Harald Stenmark

Late endosomes and lysosomes (endolysosomes) receive proteins and cargo from the secretory, endocytic and autophagic pathways. Although these pathways and the degradative processes of endolysosomes are well characterized, less is understood about protein traffic from these organelles. In this study, we demonstrate the direct involvement of the phosphatidylinositol 3-phosphate (PI3P)-binding SNX4 protein in membrane protein recycling from endolysosomes, and show that SNX4 is required for proper autophagic flux. We show that SNX4 mediates recycling of the lipid scramblase ATG9A, which drives expansion of nascent autophagosome membranes, from endolysosomes to early endosomes, from where ATG9A is recycled to the trans-Golgi network in a retromer-dependent manner. Upon siRNA-mediated depletion of SNX4 or the retromer component VPS35, we observed accumulation of ATG9A on endolysosomes and early endosomes, respectively. Moreover, starvation-induced autophagosome biogenesis and autophagic flux were inhibited when SNX4 was downregulated. We propose that proper ATG9A recycling by SNX4 sustains autophagy by preventing exhaustion of the available ATG9A pool.This article has an associated First Person interview with the first author of the paper.

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Gold(III) chloride trihydrate, ≥99.9% trace metals basis
Magnesium acetate solution, BioUltra, for molecular biology, ~1 M in H2O
Epoxy Embedding Medium kit, embedding resin for electron microscopy
Saponin from quillaja bark, Sapogenin content ≥10 %
Anti-LAMP1 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
StableCell DMEM - high glucose, With 4500 mg/L glucose, stable glutamine, and sodium bicarbonate, without sodium pyruvate., liquid, sterile-filtered, suitable for cell culture
TWEEN® 20, viscous liquid
Digitonin, Used as non-ionic detergent