Lowe syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL in Dictyostelium discoideum

Mol Biol Cell. 2019 Aug 1;30(17):2268-2282. doi: 10.1091/mbc.E18-08-0510. Epub 2019 Jun 19.


Mutations of the inositol 5-phosphatase OCRL cause Lowe syndrome (LS), characterized by congenital cataract, low IQ, and defective kidney proximal tubule resorption. A key subset of LS mutants abolishes OCRL's interactions with endocytic adaptors containing F&H peptide motifs. Converging unbiased methods examining human peptides and the unicellular phagocytic organism Dictyostelium discoideum reveal that, like OCRL, the Dictyostelium OCRL orthologue Dd5P4 binds two proteins closely related to the F&H proteins APPL1 and Ses1/2 (also referred to as IPIP27A/B). In addition, a novel conserved F&H interactor was identified, GxcU (in Dictyostelium) and the Cdc42-GEF FGD1-related F-actin binding protein (Frabin) (in human cells). Examining these proteins in D. discoideum, we find that, like OCRL, Dd5P4 acts at well-conserved and physically distinct endocytic stations. Dd5P4 functions in coordination with F&H proteins to control membrane deformation at multiple stages of endocytosis and suppresses GxcU-mediated activity during fluid-phase micropinocytosis. We also reveal that OCRL/Dd5P4 acts at the contractile vacuole, an exocytic osmoregulatory organelle. We propose F&H peptide-containing proteins may be key modifiers of LS phenotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Dictyostelium / metabolism*
  • Endocytosis / genetics
  • Endocytosis / physiology
  • Endosomes / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Inositol Polyphosphate 5-Phosphatases / metabolism
  • Kinetics
  • Membranes / metabolism
  • Mutation
  • Oculocerebrorenal Syndrome / genetics
  • Oculocerebrorenal Syndrome / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphoric Monoester Hydrolases / physiology
  • Pinocytosis
  • Protein Binding
  • Vacuoles / metabolism


  • Guanine Nucleotide Exchange Factors
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human
  • Inositol Polyphosphate 5-Phosphatases