Snazarus and its human ortholog SNX25 regulate autophagic flux by affecting VAMP8 endocytosis

Autophagy, the degradation and recycling of cytosolic components in the lysosome, is an essential cellular mechanism. It is a membrane-mediated process that is linked to vesicular trafficking events. The sorting nexin (SNX) protein family controls the sorting of a large array of cargoes, and various SNXs can impact autophagy. To gain a better understanding of their functionsin vivounder nutrient starvation, we screened allDrosophilaSNXs by RNAi in the fat body. Significantly, depletion ofsnazarus(snz) strongly impacted autolysosome formation and led to decreased autophagic flux. Interestingly, we observed altered distribution of Vamp7-positive vesicles with snz depletion andsnzroles were conserved in human cells.SNX25is the closest ortholog tosnz, and we demonstrate a role for it in VAMP8 trafficking. We found that this activity was dependent on theSNX25PX domain, and independent ofSNX25anchoring at the ER. We also demonstrate that differentially spliced forms ofSNX14andSNX25are present in cancer cells. This work identifies a conserved role forsnz/SNX25as regulators of autophagic flux, and show differential isoform expression between orthologs.