OCRL controls trafficking through early endosomes via PtdIns4,5P 2-dependent regulation of endosomal actin

Mariella Vicinanza, Antonella Di Campli, Elena Polishchuk, Michele Santoro, Giuseppe Di Tullio, Anna Godi, Elena Levtchenko, Maria Giovanna De Leo, Roman Polishchuk, Lisette Sandoval, Maria Paz Marzolo, Maria Antonietta De Matteis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)

Abstract

Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P 2) 5-phosphatase OCRL cause Lowe syndrome, which is characterised by congenital cataracts, central hypotonia, and renal proximal tubular dysfunction. Previous studies have shown that OCRL interacts with components of the endosomal machinery; however, its role in endocytosis, and thus the pathogenic mechanisms of Lowe syndrome, have remained elusive. Here, we show that via its 5-phosphatase activity, OCRL controls early endosome (EE) function. OCRL depletion impairs the recycling of multiple classes of receptors, including megalin (which mediates protein reabsorption in the kidney) that are retained in engorged EEs. These trafficking defects are caused by ectopic accumulation of PtdIns4,5P 2 in EEs, which in turn induces an N-WASP-dependent increase in endosomal F-actin. Our data provide a molecular explanation for renal proximal tubular dysfunction in Lowe syndrome and highlight that tight control of PtdIns4,5P 2 and F-actin at the EEs is essential for exporting cargoes that transit this compartment.

Original languageEnglish
Pages (from-to)4970-4985
Number of pages16
JournalEMBO Journal
Volume30
Issue number24
DOIs
Publication statusPublished - 14 Dec 2011

Keywords

  • Lowe syndrome
  • actin
  • early endosomes
  • megalin
  • phosphoinositides

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