The yeast inositol polyphosphate 5-phosphatase Inp54p localizes to the endoplasmic reticulum via a C-terminal hydrophobic anchoring tail - Regulationof secretion from the endoplasmic

budding yeast Saccharomyces cerevisiae has four inositol polyphosphate B-ph osphatase (5-phosphatase) genes, INP51, INP52, INP53, and INP54, all of whi ch hydrolyze phosphatidylinositol (4,5)-bisphosphate. INP54 encodes a prote in of 44 kDa which consists of a 5-phosphatase domain and a C-terminal leuc ine-rich tail, but lacks the N-terminal SacI domain and proline-rich region found in the other three yeast 5-phosphatases. We report that Inp54p belon gs to the family of tail-anchored proteins and is localized to the endoplas mic reticulum via a C-terminal hydrophobic tail. The hydrophobic tail compr ises the last 13 amino acids of the protein and is sufficient to target gre en fluorescent protein to the endoplasmic reticulum. Protease protection as says demonstrated that the N terminus of Inp54p is oriented toward the cyto plasm of the cell, with the C terminus of the protein also exposed to the c ytosol. Null mutation of INP54 resulted in a 2-fold increase in secretion o f a reporter protein, compared with wild-type yeast or cells deleted for an y of the SacI domain-containing Ei-phosphatases. We propose that Inp54p pla ys a role in regulating secretion, possibly by modulating the levels of pho sphatidylinositol (4,5)-bisphosphate on the cytoplasmic surface of the endo plasmic reticulum membrane.