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PMID: 21971085 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

OCRL controls trafficking through early endosomes via PtdIns4,5P₂-dependent regulation of endosomal actin.

The EMBO journal ·Vol. 30 ·No. 24 ·2011-10-04 ·Pages 4970-85

Vicinanza M, Di Campli A, Polishchuk E, Santoro M, Di Tullio G, Godi A, Levtchenko E, De Leo MG, Polishchuk R, Sandoval L, Marzolo MP, De Matteis MA

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.

MeSH Terms
Actins/metabolism Biological Transport Catalysis Cell Line Endocytosis Endosomes/enzymology,metabolism Humans Intracellular Membranes/metabolism Kidney Tubules, Proximal/metabolism Low Density Lipoprotein Receptor-Related Protein-2/metabolism Oculocerebrorenal Syndrome/genetics,metabolism Phosphatidylinositol 4,5-Diphosphate/metabolism Phosphoric Monoester Hydrolases/genetics,metabolism Polymerization
Chemicals
Actins Low Density Lipoprotein Receptor-Related Protein-2 Phosphatidylinositol 4,5-Diphosphate Phosphoric Monoester Hydrolases OCRL protein, human
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Vicinanza Mariella
Telethon Institute of Genetics and Medicine, Naples, Italy.
Di Campli Antonella
Polishchuk Elena
Santoro Michele
Di Tullio Giuseppe
Godi Anna
Levtchenko Elena
De Leo Maria Giovanna
Polishchuk Roman
Sandoval Lisette
Marzolo Maria-Paz
De Matteis Maria Antonietta
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2011.354
Published
2011-10-04
Epub
2011-00-04
Pages
4970-85
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3242071
Subset
IM
Grants
Telethon · GGP06166 · Italy
Telethon · GSP08002 · Italy
Telethon · GTF08001 · Italy
External Links
PubMed source DOI: 10.1038/emboj.2011.354 PMC Full Text View journal details
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