Inositol 5-phosphatases: Insights from the Lowe syndrome protein OCRL

Yale University, New Haven, Connecticut, United States
Trends in Biochemical Sciences (Impact Factor: 11.23). 02/2012; 37(4):134-43. DOI: 10.1016/j.tibs.2012.01.002
Source: PubMed


The precise regulation of phosphoinositide lipids in cellular membranes is crucial for cellular survival and function. Inositol 5-phosphatases have been implicated in a variety of disorders, including various cancers, obesity, type 2 diabetes, neurodegenerative diseases and rare genetic conditions. Despite the obvious impact on human health, relatively little structural and biochemical information is available for this family. Here, we review recent structural and mechanistic work on the 5-phosphatases with a focus on OCRL, whose loss of function results in oculocerebrorenal syndrome of Lowe and Dent 2 disease. Studies of OCRL emphasize how the actions of 5-phosphatases rely on both intrinsic and extrinsic membrane recognition properties for full catalytic function. Additionally, structural analysis of missense mutations in the catalytic domain of OCRL provides insight into the phenotypic heterogeneity observed in Lowe syndrome and Dent disease.


Available from: Pietro De Camilli, Aug 30, 2015
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    • "While synaptojanin 1 has a major role at synapses (Cremona et al., 1999; Harris et al., 2000; Verstreken et al., 2003), OCRL appears to be the dominant endocytic 5­phosphatase in nonneuronal cells (Zhang et al., 1998; Nández et al., 2014). A close homologue of OCRL, INPP5B, is also expressed by mammalian genomes and coop­ erates with OCRL in PI(4,5)P 2 /PI(3,4,5)P 3 dephosphorylation on endocytic membranes (Shin et al., 2005; Pirruccello and De Camilli, 2012). Neither OCRL nor INPP5B, however, con­ tain a Sac domain. "
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    ABSTRACT: The recruitment of inositol phosphatases to endocytic membranes mediates dephosphorylation of PI(4,5)P2, a phosphoinositide concentrated in the plasma membrane, and prevents its accumulation on endosomes. The importance of the conversion of PI(4,5)P2 to PtdIns during endocytosis is demonstrated by the presence of both a 5-phosphatase and a 4-phosphatase (Sac domain) module in the synaptojanins, endocytic PI(4,5)P2 phosphatases conserved from yeast to humans and the only PI(4,5)P2 phosphatases in yeast. OCRL, another 5-phosphatase that couples endocytosis to PI(4,5)P2 dephosphorylation, lacks a Sac domain. Here we show that Sac2/INPP5F is a PI4P phosphatase that colocalizes with OCRL on endocytic membranes, including vesicles formed by clathrin-mediated endocytosis, macropinosomes, and Rab5 endosomes. An OCRL-Sac2/INPP5F interaction could be demonstrated by coimmunoprecipitation and was potentiated by Rab5, whose activity is required to recruit Sac2/INPP5F to endosomes. Sac2/INPP5F and OCRL may cooperate in the sequential dephosphorylation of PI(4,5)P2 at the 5 and 4 position of inositol in a partnership that mimics that of the two phosphatase modules of synaptojanin. © 2015 Nakatsu et al.
    The Journal of Cell Biology 04/2015; 209(1):85-95. DOI:10.1083/jcb.201409064 · 9.83 Impact Factor
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    • "Phosphoinositide levels are dynamically and spatially regulated by kinases and phosphatases, establishing a code of membrane identity (Di Paolo and De Camilli, 2006; Vicinanza et al., 2008; Balla, 2013). The human genome contains 10 genes encoding inositol 5-phosphatases, a group of enzymes that dephosphorylate the inositol ring at the 5 position, nine of which act on inositol phospholipids (Dyson et al., 2012; Pirruccello and De Camilli, 2012). Mutations in one such gene, OCRL, give rise to Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and type 2 Dent's disease, two X-linked diseases (Attree et al., 1992; Hoopes et al., 2005). "
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    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. DOI:
    eLife Sciences 08/2014; 3:e02975. DOI:10.7554/eLife.02975 · 9.32 Impact Factor
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    • "TSPYL2 is a nucleosome assembly protein and is required for cell cycle maintenance under stress conditions such as DNA damage [39]. OCRL is inositol 5-phosphatase, and loss of function of this protein results in oculocerebrorenal syndrome of Lowe [40]. Although the hyopomethylated region of the genes is unlikely to be involved in regulation of the gene expression, the incidence of aberrant hypomethylation, especially of TSPYL2, is comparable to the incidence of the MED12 mutations. "
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    ABSTRACT: We recently found that aberrant DNA hypomethylation is more common on the X chromosome than on other chromosomes in uterine leiomyomas by genome-wide DNA methylation profiling. To investigate the mechanism of aberrant hypomethylation on the X chromosome in uterine leiomyomas, we analyzed methylome and transcriptome data from three cases of leiomyomas and the adjacent myometrium. We found that eleven of the aberrantly hypomethylated genes on the X chromosome were common to the three cases. None of these 11 genes were transcriptionally upregulated in the leiomyoma. However, one of them, TSPYL2, was hypomethylated in 68% of multiple leiomyoma specimens. The incidence of aberrant hypomethylation of TSPYL2 was comparable to that of the MED12 mutation (68%), which is known to be detected at a high frequency in uterine leiomyomas. We also analyzed the aberration of the X chromosome inactivation (XCI) mechanism in uterine leiomyomas. Hypomethylation was not enriched in the imprinted genes, suggesting that dysfunction of polycomb repressive complexes is not involved in the aberrant hypomethylation on the X chromosome. The expression analysis of XCI-related genes revealed that the XIST and SATB1 expression was downregulated in 36% and 46% of 11 leiomyoma specimens, respectively, while the HNRNPU and SMCHD1 expression was not altered. In conclusion, the aberration of XCI-related genes such as SATB1 or XIST may be involved in aberrant hypomethylation on the X chromosome in a certain population of the patients with uterine leiomyomas. TSPYL2 of the aberrantly hypomethylated genes on the X chromosome can be used as a biomarker of uterine leiomyomas.
    Journal of Reproduction and Development 11/2013; 60(1). DOI:10.1262/jrd.2013-095 · 1.52 Impact Factor
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