OCRL-mediated vesicular transport
Prof. Dr. Kerstin Kutsche (2008 – 2017)
University Medical Center Hamburg-Eppendorf, Institute of Human Genetics
Lowe syndrome (LS) is a rare X-linked disease characterized by mental retardation, congenital cataract, and selective proximal tubulopathy. LS is caused by mutations in the OCRL (oculocerebrorenal syndrome of Lowe) gene encoding the ubiquitously expressed inositol polyphosphate 5-phosphatase OCRL which hydrolyzes phosphoinositol phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol 4-phosphate. Binding of OCRL to different interaction partners is responsible for its localization to the TGN, early endosomes, clathrin-coated transport intermediates, and plasma membrane ruffles. We put forward the hypothesis that OCRL plays a role in intracellular trafficking processes. We could exclude a general function of OCRL in clathrin-mediated endocytosis of the transferrin and EGF receptor by performing various internalization experiments in fibroblasts from patients with LS and HeLa cells depleted of OCRL. However, in LS fibroblasts we found a significantly decreased uptake of the lysosomal enzyme arylsulfatase B, which is internalized via the mannose 6-phosphate receptor (MPR). In OCRL knockdown cells, we detected an increased amount of cell-surface MPR that is paralled by an increase in MPR internalization. By using an in vivo endosome-to-TGN transport assay, we observed that retrograde transport is reduced by ~50% in OCRL-depleted cells; this likely leads to redistribution of the MPR to maturing early-to-late endosome intermediates positive for the retromer component SNX1. The 5-phosphatase domain is essential for the function of OCRL in retrograde MPR transport suggesting that local PI(4,5)P2 dephosphorylation on the early endosomal compartment is an important trigger for endosome-to-TGN transport.