OCRL regulates lysosomal function and endolysosomal homeostasis in Drosophila nephrocytes

Abstract

The OCRL gene encodes a lipid phosphatase that dephosphorylates phosphatidylinositol 4,5 bisphosphate [(PI(4,5)P2]. Mutations in OCRL lead to a rare human genetic disorder, Lowe syndrome (LS) that affects the eye, kidney and brain. OCRL is widely expressed in cells and is localized to multiple organelles, including the plasma membrane, endosomes, Golgi and lysosomes. Although multiple defects in the endo-lysosomal system have been reported in OCRL depleted cells, the primary site of action of OCRL is unclear. Here we present a Drosophila nephrocyte model of LS; depletion of Drosophila OCRL (dOCRL) manifests with defects in endocytic uptake, altered endosomal compartments as well as expanded but dysfunctional lysosomes. Reconstitution of dOCRL depleted nephrocytes with a lysosome targeted version of the enzyme rescues not only the lysosomal defects but surprisingly also defects in endosomal structure and function. These findings suggest that the primary defect in LS cells is likely to be altered lysosome structure and function. Therefore, regulation of PI(4,5)P2 homeostasis at the lysosome membrane by OCRL is critical to homeostasis of the endosomal system.