Influence of Inositol Pyrophosphates on Cellular Energy Dynamics

Szíjgyártó, Zsolt; Garedew, Assegid; Azevedo, Cristina; Saiardi, Adolfo

doi:10.1126/science.1211908

Cited by 221 publications

(273 citation statements)

References 36 publications

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“…Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP 7 , but not 1-IP 7 , exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP 6 . Synaptotagmin 1 (Syt1), a Ca 2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP 7 .…”

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confidence: 99%

“…We report here that elevated 5-IP 7 levels, caused by overexpression of inositol hexakisphosphate (IP 6 ) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP 7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses.…”

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confidence: 99%

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Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Lee

Kyung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7–dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

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confidence: 99%

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Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Lee

Kyung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Inositol pyrophosphates have gained recent attention as signaling molecules in amoeba, yeast, and mammalian cells (Mulugu et al, 2007;Shears, 2009;Chakraborty et al, 2011;Szijgyarto et al, 2011;Wundenberg and Mayr, 2012;Pöhlmann et al, 2014). Here, we describe the presence of InsP 7 and InsP 8 in the model plant Arabidopsis and show that VIH2 is a functional inositol pyrophosphate synthetase responsible for InsP 8 production, playing a critical role in jasmonate-regulated defenses.…”

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confidence: 99%

VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP₈ and Jasmonate-Dependent Defenses in Arabidopsis

et al. 2015

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ORCID IDs: 0000-0002-7823-5489 (D.L.); 0000-0002-4512-9508 (P.J.); 0000-0002-1025-9484 (H.J.J.); 0000-0001-9022-4515 (G.S.)Diphosphorylated inositol polyphosphates, also referred to as inositol pyrophosphates, are important signaling molecules that regulate critical cellular activities in many eukaryotic organisms, such as membrane trafficking, telomere maintenance, ribosome biogenesis, and apoptosis. In mammals and fungi, two distinct classes of inositol phosphate kinases mediate biosynthesis of inositol pyrophosphates: Kcs1/IP6K-and Vip1/PPIP5K-like proteins. Here, we report that PPIP5K homologs are widely distributed in plants and that Arabidopsis thaliana VIH1 and VIH2 are functional PPIP5K enzymes. We show a specific induction of inositol pyrophosphate InsP 8 by jasmonate and demonstrate that steady state and jasmonate-induced pools of InsP 8 in Arabidopsis seedlings depend on VIH2. We identify a role of VIH2 in regulating jasmonate perception and plant defenses against herbivorous insects and necrotrophic fungi. In silico docking experiments and radioligand binding-based reconstitution assays show highaffinity binding of inositol pyrophosphates to the F-box protein COI1-JAZ jasmonate coreceptor complex and suggest that coincidence detection of jasmonate and InsP 8 by COI1-JAZ is a critical component in jasmonate-regulated defenses.

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“…In yeast, the level of polyP is metabolically connected to the level of inositol pyrophosphates (17). These molecules (InsP 7 and InsP 8 ) are notable for their ability to control cellular ATP synthesis (32,33). Because polyP influences the level of ATP in vegetatively growing cells (Fig.…”

Section: Altered Atp and Accumulation Of Inositol Pyrophosphates In Pmentioning

confidence: 99%

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

Livermore

Chubb

Saiardi

2016

Proc. Natl. Acad. Sci. U.S.A.

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Inorganic polyphosphate (polyP) is composed of linear chains of phosphate groups linked by high-energy phosphoanhydride bonds. However, this simple, ubiquitous molecule remains poorly understood. The use of nonstandardized analytical methods has contributed to this lack of clarity. By using improved polyacrylamide gel electrophoresis we were able to visualize polyP extracted from Dictyostelium discoideum. We established that polyP is undetectable in cells lacking the polyphosphate kinase (DdPpk1). Generation of this ppk1 null strain revealed that polyP is important for the general fitness of the amoebae with the mutant strain displaying a substantial growth defect. We discovered an unprecedented accumulation of polyP during the developmental program, with polyP increasing more than 100-fold. The failure of ppk1 spores to accumulate polyP results in a germination defect. These phenotypes are underpinned by the ability of polyP to regulate basic energetic metabolism, demonstrated by a 2.5-fold decrease in the level of ATP in vegetative ppk1. Finally, the lack of polyP during the development of ppk1 mutant cells is partially offset by an increase of both ATP and inositol pyrophosphates, evidence for a model in which there is a functional interplay between inositol pyrophosphates, ATP, and polyP.inorganic polyphosphate | phosphate | metabolism | inositol pyrophosphate | mitochondria T he simplest biological polymer is inorganic polyphosphate (polyP), which consists of a linear chain of phosphates linked by high-energy phosphoanhydride bonds (1). Regardless of its origin, polyP is ubiquitously present in today's living organisms. The synthesis, enzymology, and role of polyP are best characterized in the bacteria Escherichia coli (2). However, polyP is also present in archaea (3), eukaryotes (4), and human cells (5). Whilst polyP is present in virtually all cellular compartments (6), it accumulates in acidocalcisomes, organelles common to bacteria and mammalian cells (7).PolyP has been implicated in a range of cellular processes over recent years, but its most basic proposed function is to act as a buffer for the level of free phosphate (8). Phosphate buffering is essential for general metabolism, and the synthesis or degradation of polyP is able to safeguard the level of free phosphate in cells. In addition, the polyanionic nature of polyP makes it a strong chelator of bivalent cations; thus polyP plays a key role in cation homeostasis. The chelation of calcium by polyP might even play a role as a calcium sink, regulating calcium signaling (8). Besides these common roles, many specific functions have been attributed to polyP in eukaryotes (see reviews in refs. 9-11). Recently its ability to function as a protein-folding chaperone (12) and to drive a newly discovered posttranslational protein modification, protein polyphosphorylation (13), have provided further insight into the mechanism of action of this simple polymer.Little is known about the synthesis or metabolism of polyP in eukaryotes. The yeast Saccharomyces c...

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Influence of Inositol Pyrophosphates on Cellular Energy Dynamics

Cited by 221 publications

References 36 publications

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP₈ and Jasmonate-Dependent Defenses in Arabidopsis

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

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Influence of Inositol Pyrophosphates on Cellular Energy Dynamics

Cited by 221 publications

References 36 publications

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP8 and Jasmonate-Dependent Defenses in Arabidopsis

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

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VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP₈ and Jasmonate-Dependent Defenses in Arabidopsis