PT  - JOURNAL ARTICLE
AU  - Anthony Ravussin
AU  - Sharon A. Tooze
AU  - Harald Stenmark
TI  - The phosphatidylinositol 3-phosphate binding protein SNX4 controls ATG9A recycling and autophagy
AID  - 10.1101/2020.06.24.169193
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.24.169193
4099  - http://biorxiv.org/content/early/2020/06/24/2020.06.24.169193.short
4100  - http://biorxiv.org/content/early/2020/06/24/2020.06.24.169193.full
AB  - Late endosomes and lysosomes (endolysosomes) receive proteins and cargo from the secretory, endocytic and autophagic pathways. Whereas 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 transmembrane autophagy machinery protein ATG9A 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. Altogether, we propose that proper ATG9A recycling by SNX4 sustains autophagy by preventing exhaustion of the available ATG9A pool.