Abstract
Lowe Syndrome is a rare recessive, X-linked disease caused by mutations in the OCRL gene, which encodes a phosphoinositide phosphatase. Lowe Syndrome is caused by loss of the phosphoinositide phosphatase OCRL. While a significant amount is understood about the activities of this protein in vitro, very little is known about how loss of these activities lead to disease pathology including renal failure, congenital cataracts, cognitive problems, seizures and hypotonia. OCRL has been proposed to inhibit actin filament assembly either through its 5-phosphatase domain or through its RhoGAP domain. We generated a null mutant of the single Drosophila OCRL homolog, dOCRL, and found that the 5-phosphatase domain plays critical roles in attenuating levels of PI(4,5)P2 and PI(3,4,5)P3 in the endocytic pathway that controls innate immune signaling in hemocytes. Further, we found that dOCRL inhibits SCAR-dependent actin filament assembly in these cells via its 5-phosphatase activity. Our final working model sheds light on the mechanism of the 5-phosphatase domain and raises question about the importance of the RhoGAP domain for the physiological function of dOCRL.