Inositol pyrophosphates: between signalling and metabolism.
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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ABSTRACT: Ribosome biogenesis is an essential cellular process regulated by the metabolic state of a cell. We examined whether inositol pyrophosphates, energy-rich derivatives of inositol which act as metabolic messengers, play a role in ribosome synthesis in the budding yeast, Saccharomyces cerevisiae. Yeast lacking the IP6 kinase Kcs1, which is required for the synthesis of inositol pyrophosphates, display increased sensitivity to translation inhibitors and decreased protein synthesis. These phenotypes are reversed upon the expression of enzymatically active Kcs1, but not the inactive form. kcs1Δ yeast exhibit reduced levels of ribosome subunits, suggesting that they are defective in ribosome biogenesis. The rate of rRNA synthesis, the first step of ribosome biogenesis, is decreased in kcs1Δ yeast, suggesting that RNA polymerase I (Pol I) activity may be reduced in these cells. We determined that the Pol I subunits, A190, A43 and A34.5 can accept a β phosphate moiety from inositol pyrophosphates to undergo serine pyrophosphorylation. Although there is impaired rRNA synthesis in kcs1Δ yeast, we did not find any defect in recruitment of Pol I on rDNA, but observe that the rate of transcription elongation is compromised. Taken together, our findings highlight inositol pyrophosphates as novel regulators of rRNA transcription.Biochemical Journal 11/2014; 466(1). DOI:10.1042/BJ20140798 · 4.78 Impact Factor
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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.Molecular Cell 03/2015; DOI:10.1016/j.molcel.2015.02.010 · 14.46 Impact Factor
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ABSTRACT: In eukaryotic cells, type 4 P-type ATPases function as phospholipid flippases, which translocate phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet of the lipid bilayer. Flippases function in the formation of transport vesicles, but the mechanism remains unknown. Here, we isolate an arrestin-related trafficking adaptor, ART5, as a multicopy suppressor of the growth and endocytic recycling defects of flippase mutants in budding yeast. Consistent with a previous report that Art5p downregulates the inositol transporter Itr1p by endocytosis, we found that flippase mutations were also suppressed by the disruption of ITR1, as well as by depletion of inositol from the culture medium. Interestingly, inositol depletion suppressed the defects in all five flippase mutants. Inositol depletion also partially restored the formation of secretory vesicles in a flippase mutant. Inositol depletion caused changes in lipid composition, including a decrease in phosphatidylinositol and an increase in phosphatidylserine. A reduction in phosphatidylinositol levels caused by partially depleting the phosphatidylinositol synthase Pis1p also suppressed a flippase mutation. These results suggest that inositol depletion changes the lipid composition of the endosomal/TGN membranes, which results in vesicle formation from these membranes in the absence of flippases.PLoS ONE 10(3):e0120108. DOI:10.1371/journal.pone.0120108 · 3.53 Impact Factor