Article

PI4P and PI(4,5)P-2 Are Essential But Independent Lipid Determinants of Membrane Identity

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Science (Impact Factor: 33.61). 06/2012; 337(6095):727-30. DOI: 10.1126/science.1222483
Source: PubMed

ABSTRACT

The quantitatively minor phospholipid phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] fulfills many cellular functions in the plasma membrane (PM), whereas its synthetic precursor, phosphatidylinositol 4-phosphate
(PI4P), has no assigned PM roles apart from PI(4,5)P2 synthesis. We used a combination of pharmacological and chemical genetic approaches to probe the function of PM PI4P, most
of which was not required for the synthesis or functions of PI(4,5)P2. However, depletion of both lipids was required to prevent PM targeting of proteins that interact with acidic lipids or activation
of the transient receptor potential vanilloid 1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids
that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P2, which may be fulfilled by a more general polyanionic lipid requirement.

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Available from: Michael J.M. Fischer, Dec 17, 2013
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    • "At the plasma membrane the lipid is generated by the Inp51-mediated catabolism of PI(4,5)P 2 or by the phosphorylation of PI by the PI 4-kinase Stt4[19]. Knowledge of its role at the plasma membrane , apart from PI(4,5)P 2 synthesis, is scarce, although recent reports suggest that the majority of PI(4)P resides in this location[37]and plays an essential function as determinant of membrane identity[38]. We observed that overexpression of STT4, which is expected to cause increased abundance of plasma membrane PI(4)P, stimulated the yeast growth at low temperature. "
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    ABSTRACT: Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its derivatives diphosphoinositol phosphates (DPIPs) play key signaling and regulatory roles. However, a direct function of these molecules in lipid and membrane homeostasis remains obscure. Here, we have studied the cold tolerance phenotype of yeast cells lacking the Inp51-mediated phosphoinositide-5-phosphatase. Genetic and biochemical approaches showed that increased metabolism of PI(4,5)P2 reduces the activity of the Pho85 kinase by increasing the levels of the DPIP isomer 1-IP7. This effect was key in the cold tolerance phenotype. Indeed, pho85 mutant cells grew better than the wild-type at 15 °C, and lack of this kinase abolished the inp51-mediated cold phenotype. Remarkably, reduced Pho85 function by loss of Inp51 affected the activity of the Pho85-regulated target Pah1, the yeast phosphatidate phosphatase. Cells lacking Inp51 showed reduced Pah1 abundance, derepression of an INO1-lacZ reporter, decreased content of triacylglycerides and elevated levels of phosphatidate, hallmarks of the pah1 mutant. However, the inp51 phenotype was not associated to low Pah1 activity since deletion of PAH1 caused cold sensitivity. In addition, the inp51 mutant exhibited features not shared by pah1, including a 40%-reduction in total lipid content and decreased membrane fluidity. These changes may influence the activity of membrane-anchored and/or associated proteins since deletion of INP51 slows down the transit to the vacuole of the fluorescent dye FM4-64. In conclusion, our work supports a model in which changes in the PI(4,5)P2 pool affect the 1-IP7 levels modulating the activity of Pho85, Pah1 and likely additional Pho85-controlled targets, and regulate lipid composition and membrane properties.
    Full-text · Article · Dec 2015 · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
    • "In contrast to the PM, which contains levels of PI4P far in excess of those needed to support basal PI(4,5)P2 synthesis (Hammond et al., 2012), in primary cilia it appears that ciliary PI(4,5)P2 hydrolysis by INPP5E is the likely source of PI4P. Indeed, upon INPP5E inactivation, PI(4,5)P2 accumulates in cilia along with depletion of PI4P from the ciliary compartment (Figures 2B, 3A, and 3B), thus suggesting that PI(4,5)P2 is unable to be dephosphorylated to PI4P. "
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    ABSTRACT: Ciliary transport is required for ciliogenesis, signal transduction, and trafficking of receptors to the primary cilium. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) have been associated with ciliary dysfunction; however, its role in regulating ciliary phosphoinositides is unknown. Here we report that in neural stem cells, phosphatidylinositol 4-phosphate (PI4P) is found in high levels in cilia whereas phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is not detectable. Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted. This is accompanied by recruitment of the PI(4,5)P2-interacting protein TULP3 to the ciliary membrane, along with Gpr161. This results in an increased production of cAMP and a repression of the Shh transcription gene Gli1. Our results reveal the link between ciliary regulation of phosphoinositides by INPP5E and Shh regulation via ciliary trafficking of TULP3/Gpr161 and also provide mechanistic insight into ciliary alterations found in Joubert and MORM syndromes resulting from INPP5E mutations. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Developmental Cell
    • "A known player is INPP5E, which is able to convert PtdIns(4,5)P 2 into PtdIns(4)P (Fig. 1). Consistently, depletion of this phosphatase decreases TfR internalization rate [42]. Similarly, down-modulation of INPP4A (type I a "
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    ABSTRACT: The spatial restriction of phosphorylated phosphoinositides generated downstream activated membrane receptors is critical for proper cell response to environmental cues. The α isoform of class II PI3Ks, PI3K-C2α, has emerged as a modulator of receptor localization, acting both in the control of receptor endocytosis and resensitization. This unexpectedly versatile enzyme was found to differentially produce two distinct 3-phosphorylated phosphoinositides and to selectively control distinct steps of vesicular traffic such as endocytosis and recycling. This review focuses on the latest discoveries regarding PI3K-C2α function in vesicle trafficking and its impact on cell biology and mammalian embryonic development. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · May 2015 · FEBS letters
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