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OCRL controls trafficking through early endosomes via PtdIns4,5P 2 ‐dependent regulation of endosomal actin
Author(s) -
Vicinanza Mariella,
Di Campli Antonella,
Polishchuk Elena,
Santoro Michele,
Di Tullio Giuseppe,
Godi Anna,
Levtchenko Elena,
De Leo Maria Giovanna,
Polishchuk Roman,
Sandoval Lisette,
Marzolo MariaPaz,
De Matteis Maria Antonietta
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.354
Subject(s) - endosome , humanities , biology , library science , genetics , art , computer science , cell
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.