Targeting of the lipid phosphatase OCRL1 to the Golgi apparatu

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked genetic disorder affecting the lens, kidney and central nervous system. It has been shown that mutation of the gene encoding OCRL1 protein is the cause of Lowe syndrome. OCRL1 is a phosphatidylinositol(4,5)bisphosphate 5-phosphatase [PI(4,5)P2 5-phosphatase]. It is a Golgi-associated 105-kDa peripheral membrane protein. The cellular role of OCRL1 is not known and it is also not established how OCRL1 associates with or is targeted to the Golgi apparatus. Therefore, the mechanism by which loss of OCRL1 function leads to Lowe syndrome is unclear. The findings in this study show that the C-terminus of OCRL1 is required for targeting to the Golgi apparatus. The data also demonstrate that OCRL1 is present on endosomes and clathrin-coated transport intermediates operating between the trans-Golgi network (TGN) and endosomes. Biochemical studies show that OCRL1 directly interacts with the terminal domain of the clathrin heavy chain (CHC). Over-expression of 5-phosphatase deficient OCRL1 mutants causes fragmentation of the Golgi ribbon and redistribution of clathrin and the cation-independent mannose-6-phosphate receptor (CI-MPR) to endosomal compartments. In addition, small interfering RNA (siRNA)- mediated depletion of cellular OCRL1 results in partial redistribution of the CI-MPR to morphologically altered early endosomes. These data indicate a role for OCRL1 in regulating clathrin-mediated trafficking of proteins at the TGN/endosome interface and suggest that defects in trafficking between these compartments may lead to the Lowe syndrome phenotype.