Article

Inositol pyrophosphates: Between signalling and metabolism

Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, U.K.
Biochemical Journal (Impact Factor: 4.4). 06/2013; 452(3):369-379. DOI: 10.1042/BJ20130118
Source: PubMed

ABSTRACT

The present review will explore the insights gained into inositol pyrophosphates in the 20 years since their discovery in 1993. These molecules are defined by the presence of the characteristic 'high energy' pyrophosphate moiety and can be found ubiquitously in eukaryotic cells. The enzymes that synthesize them are similarly well distributed and can be found encoded in any eukaryote genome. Rapid progress has been made in characterizing inositol pyrophosphate metabolism and they have been linked to a surprisingly diverse range of cellular functions. Two decades of work is now beginning to present a view of inositol pyrophosphates as fundamental, conserved and highly important agents in the regulation of cellular homoeostasis. In particular it is emerging that energy metabolism, and thus ATP production, is closely regulated by these molecules. Much of the early work on these molecules was performed in the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum, but the development of mouse knockouts for IP6K1 and IP6K2 [IP6K is IP6 (inositol hexakisphosphate) kinase] in the last 5 years has provided very welcome tools to better understand the physiological roles of inositol pyrophosphates. Another recent innovation has been the use of gel electrophoresis to detect and purify inositol pyrophosphates. Despite the advances that have been made, many aspects of inositol pyrophosphate biology remain far from clear. By evaluating the literature, the present review hopes to promote further research in this absorbing area of biology.

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Available from: Adolfo Saiardi, Jan 14, 2016
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    • "But, if the phenotype of the inp51 mutant is linked to increased 1-IP 7 levels, why do cells of the kcs1 mutant exhibit a severe cold sensitivity phenotype? As mentioned above Kcs1 is able to use IP 5 as substrate to generate 5PP-IP 4 , which is then phosphorylated to (PP) 2 –IP 3 (Fig. 1)[109]. Recently, Ye et al.[113]demonstrated that Kcs1 regulates inositol biosynthesis by controlling INO1 expression. "
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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.
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    • "This PTM is highly labile in acidic conditions and thus has not been detected by available MS techniques. The molecules responsible for this PTM, inositol pyrophosphates, are characterized by the presence of highly energetic pyrophosphate moieties and are able to regulate diverse functions by affecting cellular metabolism (Chakraborty et al., 2011; Wilson et al., 2013). Inositol pyrophosphates also regulate the metabolism of inorganic polyphosphate (polyP; Lonetti et al., 2011). "
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    ABSTRACT: The complexity of higher organisms is not simply a reflection of the number of genes. A network of additional regulatory features, including protein post-translational modifications (PTMs), provides functional complexity otherwise inaccessible to a single gene product. Virtually all proteins are targets of PTMs. Here we characterize "polyphosphorylation" as the covalent attachment of inorganic polyphosphate (polyP) to target proteins. We found that nuclear signal recognition 1 (Nsr1) and its interacting partner, topoisomerase 1 (Top1), are polyphosphorylated. This modification occurs on lysine (K) residues within a conserved N-terminal polyacidic serine (S) and K-rich (PASK) cluster. We show that polyphosphorylation negatively regulates Nsr1/Top1 interaction and impairs Top1 enzymatic activity. Physiological modulation of cellular levels of polyP regulates Top1 activity by modifying its polyphosphorylation status. We propose that polyphosphorylation adds an additional layer of regulation to nuclear signaling, where many PASK-containing proteins are known to play important roles. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Molecular Cell
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    • "A unique group of InsP signaling molecules containing diphosphate or triphosphate chains (i.e. PPx-InsPs) are emerging as critical players in various signaling processes in eukaryotes, and are synthesized from higher InsP precursors (Figure 1) (Saiardi, 2012; Shears et al., 2013; Wilson et al., 2013). PPx- InsPs are thought of as 'energy-rich' molecules because pyrophosphate moieties have a free energy of hydrolysis comparable to that of ATP (Hand and Honek, 2007). "
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