A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells

Ramiro Nández, Daniel M. Balkin, Mirko Messa, Liang Liang, Summer Paradise, Heather Czapla, Marco Y. Hein, James S. Duncan, Matthias Mann, Pietro De Camilli

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations.

Original languageEnglish (US)
Article numbere02975
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume3
Issue numberAugust2014
DOIs
StatePublished - Aug 8 2014
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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