Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival.

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Inositol polyphosphate multikinase regulation ofTrypanosoma bruceilife stage development

Molecular Biology of the Cell ◽

10.1091/mbc.e17-08-0515 ◽

2018 ◽

Vol 29 (9) ◽

pp. 1137-1152 ◽

Cited By ~ 5

Author(s):

Igor Cestari ◽

Atashi Anupama ◽

Kenneth Stuart

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Inositol Phosphates ◽

Inositol Phosphate ◽

Tsetse Fly ◽

Developmental Changes ◽

Mammalian Host ◽

Surface Coat ◽

Inositol Polyphosphate ◽

Inositol Polyphosphate Multikinase

Many cellular processes change during the Trypanosoma brucei life cycle as this parasite alternates between the mammalian host and tsetse fly vector. We show that the inositol phosphate pathway helps regulate these developmental changes. Knockdown of inositol polyphosphate multikinase (IPMK), which phosphorylates Ins(1,4,5)P3 and Ins(1,3,4,5)P4, resulted in changes in bloodstream forms that are characteristic of insect stage procyclic forms. These changes include expression of the procyclic surface coat, up-regulation of RNA-binding proteins that we show to regulate stage-specific transcripts, and activation of oxidative phosphorylation with increased ATP production in bloodstream forms. These changes were accompanied by development of procyclic morphology, which also occurred by the expression of a catalytically inactive IPMK, implying that regulation of these processes entails IPMK activity. Proteins involved in signaling, protein synthesis and turnover, and metabolism were affinity-enriched with the IPMK substrate or product. Developmental changes associated with IPMK knockdown or catalytic inactivation reflected processes that are enriched with inositol phosphates, and chemical and genetic perturbation of these processes affected T. brucei development. Hence, IPMK helps regulate T. brucei development, perhaps by affecting inositol phosphate interactions with proteins of the regulatory network that controls energy metabolism and development.

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Inositol polyphosphate multikinase mediates extinction of fear memory

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812771116 ◽

2019 ◽

Vol 116 (7) ◽

pp. 2707-2712 ◽

Cited By ~ 2

Author(s):

Jina Park ◽

Francesco Longo ◽

Seung Ju Park ◽

Seulgi Lee ◽

Mihyun Bae ◽

...

Keyword(s):

Long Term Potentiation ◽

Fear Memory ◽

Fear Extinction ◽

Tissue Growth ◽

Conditional Knockout ◽

Inositol Polyphosphate ◽

Inositol Polyphosphates ◽

Term Potentiation ◽

Key Enzyme ◽

Inositol Polyphosphate Multikinase

Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by selective activation of the mechanistic target of rapamycin (mTOR) regulatory enzyme p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. The IPMK mutants also manifested facilitated hippocampal long-term potentiation. These findings establish a signaling action of IPMK that mediates fear extinction.

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Faculty Opinions recommendation of Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027855.334830 ◽

2005 ◽

Author(s):

Catherine Jackson

Keyword(s):

Pi3 Kinase ◽

Inositol Polyphosphate ◽

Regulatory Activity ◽

Transcriptional Regulatory ◽

Inositol Polyphosphate Multikinase

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Faculty Opinions recommendation of Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8693959.11171056 ◽

2011 ◽

Author(s):

Joseph Avruch ◽

Angela Papageorgiou

Keyword(s):

Amino Acid ◽

Inositol Polyphosphate ◽

Inositol Polyphosphate Multikinase ◽

Amino Acid Signaling

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Role of the Inositol Polyphosphate Multikinase Ipk2 in Regulation of Hyphal Development, Calcium Signaling and Secretion in Candida albicans

Mycopathologia ◽

10.1007/s11046-017-0138-4 ◽

2017 ◽

Vol 182 (7-8) ◽

pp. 609-623 ◽

Cited By ~ 6

Author(s):

Jianrong Li ◽

Bing Zhang ◽

Tianyu Ma ◽

Honggang Wang ◽

Biao Zhang ◽

...

Keyword(s):

Candida Albicans ◽

Calcium Signaling ◽

Inositol Polyphosphate ◽

Hyphal Development ◽

Inositol Polyphosphate Multikinase

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Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511810112 ◽

2015 ◽

Vol 112 (31) ◽

pp. 9751-9756 ◽

Cited By ~ 16

Author(s):

Ishrat Ahmed ◽

Juan I. Sbodio ◽

Maged M. Harraz ◽

Richa Tyagi ◽

Jonathan C. Grima ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Kinase Activity ◽

Inositol Phosphate ◽

Cell Model ◽

Inositol Polyphosphate ◽

Interacting Protein ◽

Lipid Kinase ◽

Inositol Polyphosphate Multikinase ◽

Neural Dysfunction

Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.

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Accumulation of inositol polyphosphate isomers in agonist-stimulated cerebral-cortex slices. Comparison with metabolic profiles in cell-free preparations

Biochemical Journal ◽

10.1042/bj2580023 ◽

1989 ◽

Vol 258 (1) ◽

pp. 23-32 ◽

Cited By ~ 46

Author(s):

I H Batty ◽

A J Letcher ◽

S R Nahorski

Keyword(s):

Cerebral Cortex ◽

Inositol Phosphates ◽

Periodate Oxidation ◽

Chemical Degradation ◽

Inositol Polyphosphate ◽

Tissue Slices ◽

Inositol 1 ◽

Agonist Stimulation ◽

Cortex Slices ◽

Hydrolysis Of

1. Basal and carbachol-stimulated accumulations of isomeric [3H]inositol mono-, bis-, tris- and tetrakis-phosphates were examined in rat cerebral-cortex slices labelled with myo-[2-3H]inositol. 2. In control samples the major [3H]inositol phosphates detected were co-eluted on h.p.l.c. with Ins(1)P, Ins(4)P (inositol 1- and 4-monophosphate respectively), Ins(1,4)P2 (inositol 1,4-bisphosphate), Ins(1,4,5)P3 (inositol 1,4,5-tris-phosphate) and Ins(1,3,4,5)P4 (inositol 1,3,4,5-tetrakisphosphate). 3. After stimulation to steady state with carbachol, accumulation of each of these products was markedly increased. 4. Agonist stimulation, however, also evoked much more dramatic increased accumulations of a second [3H]inositol trisphosphate, which was co-eluted on h.p.l.c. with authentic Ins(1,3,4)P3 (inositol 1,3,4-trisphosphate) and of three further [3H]inositol bisphosphates ([3H]InsP2(s]. 5. Examination of the latter by chemical degradation by periodate oxidation and/or h.p.l.c. allowed identification of these as [3H]Ins(1,3)P2, [3H]Ins(3,4)P2 and [3H]Ins(4,5)P2 (inositol 1,3-, 3,4- and 4,5-bisphosphates respectively), which respectively accounted for about 22%, 8% and 3% of total [3H]InsP2 in extracts from stimulated tissue slices. 6. By using a h.p.l.c. method which clearly resolves Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 (inositol 1,3,4,6-tetrakisphosphate), only the former isomer could be detected in extracts from either control or stimulated tissue slices. Similarly, [3H]inositol pentakis- and hexakis-phosphates were not detectable either in the presence or absence of carbachol under the radiolabelling conditions described. 7. The catabolism of [3H]Ins(1,4,5)P3 and [3H]Ins(1,3,4)P3 by cell-free preparations from cerebral cortex was also studied. 8. In the presence of Mg2+, [3H]Ins(1,4,5)P3 was specifically dephosphorylated via [3H]Ins(1,4)P2 and [3H]Ins(4)P to free [3H]inositol, whereas [3H]Ins(1,3,4)P3 was degraded via [3H]Ins(3,4)P2 and, to a lesser extent, via [3H]Ins(1,3)P2 to D- and/or L-[3H]Ins(1)P and [3H]inositol. 9. In the presence of EDTA, hydrolysis of [3H]Ins(1,4,5)P3 was greater than or equal to 95% inhibited, whereas [3H]Ins(1,3,4)P3 was still degraded, but yielded only a single [3H]InsP2 identified as [3H]Ins(1,3)P2. 10. The significance of these observations with cell-free preparations is discussed in relation to the proportions of the separate isomeric [3H]inositol phosphates measured in stimulated tissue slices.

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