The Inositol 5-Phosphatase dOCRL Controls PI(4,5)P2 Homeostasis and Is Necessary for Cytokinesis

Abstract

During cytokinesis, constriction of an equatorial actomyosin ring physically separates the two daughter cells. At the cleavage furrow, the phosphoinositide PI(4,5)P2 plays an important role by recruiting and regulating essential proteins of the cytokinesis machinery [1]. Accordingly, perturbation of PI(4,5)P2 regulation leads to abortive furrowing and binucleation [2-4]. To determine how PI(4,5)P2 is regulated during cytokinesis, we individually knocked down each of the enzymes controlling the phosphoinositide (PIP) cycle in Drosophila. We show that depletion of the Drosophila ortholog of human oculocerebrorenal syndrome of Lowe 1 (OCRL1), an inositol 5-phosphatase mutated in the X-linked disorder oculocerebrorenal Lowe syndrome, triggers a high rate of cytokinesis failure. In absence of dOCRL, several essential components of the cleavage furrow were found to be incorrectly localized on giant cytoplasmic vacuoles rich in PI(4,5)P2 and in endocytic markers. We demonstrate that dOCRL is associated with endosomes and that it dephosphorylates PI(4,5)P2 on internal membranes to restrict this phosphoinositide at the plasma membrane and thereby regulates cleavage furrow formation and ingression. Identification of dOCRL as essential for cell division may be important to understand the molecular basis of the phenotypic manifestations of Lowe syndrome.

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

“…Anchorage-independent growth of shRNA-transduced cells was tested according to a published method (57). …”

Phosphoinositides in endocytosis

“…These data suggest that OCRL functions as a link between late stages of endocytosis, possibly related to uncoating, and the acquisition of endosomal PI(3)P identity [84,86]. Dysfunction of OCRL is associated with endocytic defects in oculocerebrorenal syndrome of Lowe and in Dent's disease [84,86], inherited kidney disorders as well as with defective cytokinesis [143]. Trisomy for the OCRL-related brain-enriched endocytic PI(4,5)P 2 phosphatase synaptojanin 1 is linked to early endosomal defects and mental retardation in Down syndrome [144] and in Parkinson's disease [145,146].…”

Proteomics Screen Identifies Class I Rab11 Family Interacting Proteins as Key Regulators of Cytokinesis

“…Deconvolution was carried out using SoftWoRx software, version 5.5. Cells were fixed in 4% paraformaldehyde and then proceeded for immunostaining (46), while time-lapse imaging was performed in an environmental chamber at 25°C. All cell images represent a single focal plane.…”