Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors

Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P(2)), made by Fab1p, is essential for vesicle recycling from vacuole/lysosomal compartments and for protein sorting into multivesicular bodies. To isolate PtdIns(3,5)P(2) effectors, we identified Saccharomyces cerevisiae mutants that display fab1Delta-like vacuole enlargement, one of which lacked the SVP1/YFR021w/ATG18 gene. Expressed Svp1p displays PtdIns(3,5)P(2) binding of exquisite specificity, GFP-Svp1p localises to the vacuole membrane in a Fab1p-dependent manner, and Svp1Delta cells fail to recycle a marker protein from the vacuole to the Golgi. Cells lacking Svp1p accumulate abnormally large amounts of PtdIns(3,5)P(2). These observations identify Svp1p as a PtdIns(3,5)P(2) effector required for PtdIns(3,5)P(2)-dependent membrane recycling from the vacuole. Other Svp1p-related proteins, including human and Drosophila homologues, bind PtdIns(3,5)P(2) similarly. Svp1p and related proteins almost certainly fold as beta-propellers, and the PtdIns(3,5)P(2)-binding site is on the beta-propeller. It is likely that many of the Svp1p-related proteins that are ubiquitous throughout the eukaryotes are PtdIns(3,5)P(2) effectors. Svp1p is not involved in the contributions of FAB1/PtdIns(3,5)P(2) to MVB sorting or to vacuole acidification and so additional PtdIns(3,5)P(2) effectors must exist.