scholarly journals [PSI+] prion propagation is controlled by inositol polyphosphates

2017 ◽  
Vol 114 (40) ◽  
pp. E8402-E8410 ◽  
Author(s):  
Reed B. Wickner ◽  
Amy C. Kelly ◽  
Evgeny E. Bezsonov ◽  
Herman K. Edskes
Keyword(s):  
Transcription Regulation ◽  
Inositol Polyphosphate ◽  
Genetic Tests ◽  
Inositol Polyphosphates ◽  
Yeast Prions ◽  
Protein Overproduction ◽  
Prion Propagation ◽  
Regulation Functions ◽  
Inositol Polyphosphate Multikinase ◽  
Β Sheet

The yeast prions [PSI+] and [URE3] are folded in-register parallel β-sheet amyloids of Sup35p and Ure2p, respectively. In a screen for antiprion systems curing [PSI+] without protein overproduction, we detected Siw14p as an antiprion element. An array of genetic tests confirmed that many variants of [PSI+] arising in the absence of Siw14p are cured by restoring normal levels of the protein. Siw14p is a pyrophosphatase specifically cleaving the β phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5), suggesting that increased levels of this or some other inositol polyphosphate favors [PSI+] propagation. In support of this notion, we found that nearly all variants of [PSI+] isolated in a WT strain were lost upon loss of ARG82, which encodes inositol polyphosphate multikinase. Inactivation of the Arg82p kinase by D131A and K133A mutations (preserving Arg82p’s nonkinase transcription regulation functions) resulted the loss of its ability to support [PSI+] propagation. The loss of [PSI+] in arg82Δ is independent of Hsp104’s antiprion activity. [PSI+] variants requiring Arg82p could propagate in ipk1Δ (IP5 kinase), kcs1Δ (IP6 5-kinase), vip1Δ (IP6 1-kinase), ddp1Δ (inositol pyrophosphatase), or kcs1Δ vip1Δ mutants but not in ipk1Δ kcs1Δ or ddp1Δ kcs1Δ double mutants. Thus, nearly all [PSI+] prion variants require inositol poly-/pyrophosphates for their propagation, and at least IP6 or 5PP-IP4 can support [PSI+] propagation.

scholarly journals Intestinal epithelial IPMK protects mice from experimental colitis via governing colonic tuft cell development

2021 ◽  
Author(s):  
Seung Eun Park ◽  
Jae Woong Jung ◽  
Su-Hyung Lee ◽  
Seung Ju Park ◽  
Jaeseung Ryu ◽  
...  
Keyword(s):  
Experimental Colitis ◽  
Intestinal Epithelial ◽  
Inositol Polyphosphate ◽  
Critical Function ◽  
Inositol Polyphosphates ◽  
Epithelial Homeostasis ◽  
Tuft Cell ◽  
Cholinergic Signaling ◽  
Target Molecules ◽  
Inositol Polyphosphate Multikinase

As a pleiotropic signaling factor, inositol polyphosphate multikinase (IPMK) is involved in key biological events such as growth and innate immunity, acting either enzymatically to mediate the biosynthesis of inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphates, or noncatalytically to control key signaling target molecules. However, the functional significance of IPMK in regulating gut epithelial homeostasis remains largely unknown. Here we show that intestinal epithelial-specific deletion of IPMK aggravates dextran sulfate sodium (DSS)-induced colitis with higher clinical colitis scores and elevated epithelial barrier permeability. No apparent defects in PI3K-AKT signaling pathway and pro-inflammatory cytokine production were found in IPMK-deficient colons challenged by DSS treatment. RNA-sequencing and FACS analyses further revealed significantly decreased tuft cells in IPMK-deficient colons. Importantly, IPMK deletion in the gut epithelium was found to decrease choline acetyltransferase (ChAT) but not IL-25, suggesting selective loss of cholinergic signaling. Thus, these findings identify IPMK as a physiological determinant of tuft cell differentiation and highlight the critical function of IPMK in the control of gut homeostasis.

scholarly journals Inositol polyphosphate multikinase mediates extinction of fear memory

2019 ◽  
Vol 116 (7) ◽  
pp. 2707-2712 ◽  
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.

scholarly journals How Do Yeast Cells Contend with Prions?

2020 ◽  
Vol 21 (13) ◽  
pp. 4742 ◽  
Author(s):  
Reed B. Wickner ◽  
Herman K. Edskes ◽  
Moonil Son ◽  
Songsong Wu ◽  
Madaleine Niznikiewicz
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Prion Protein ◽  
Yeast Cells ◽  
Functional Amyloid ◽  
Inositol Polyphosphates ◽  
Yeast Prions ◽  
Amyloid Diseases ◽  
Infectious Proteins ◽  
Β Sheet

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.

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

2015 ◽  
Vol 112 (31) ◽  
pp. 9751-9756 ◽  
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.

scholarly journals Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling

2020 ◽  
Vol 21 (19) ◽  
pp. 7198
Author(s):  
Tania Maffucci ◽  
Marco Falasca
Keyword(s):  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Deep Understanding ◽  
Inositol Polyphosphate ◽  
Inositol Polyphosphates ◽  
Downstream Effectors ◽  
Protein Membrane ◽  
Phosphoinositide 3 Kinase ◽  
Cancer Settings ◽  
Established Role

Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a multitude of drugs, some of which have progressed into clinical trials, with few of them currently approved for use in specific cancer settings. While many inhibitors compete with ATP, hence preventing the catalytic activity of the kinases directly, a deep understanding of the mechanisms of PI3K-dependent activation of its downstream effectors led to the development of additional strategies to prevent the initiation of this signaling pathway. This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals. We focus our attention on the inhibition of protein–membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that we proposed 20 years ago as a novel therapeutic strategy.

scholarly journals Inositol Polyphosphate Multikinase Is a Coactivator of p53-Mediated Transcription and Cell Death

2013 ◽  
Vol 6 (269) ◽  
pp. ra22-ra22 ◽  
Author(s):  
R. Xu ◽  
N. Sen ◽  
B. D. Paul ◽  
A. M. Snowman ◽  
F. Rao ◽  
...  
Keyword(s):  
Cell Death ◽  
Inositol Polyphosphate ◽  
Inositol Polyphosphate Multikinase

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

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 125 ◽  
Author(s):  
Francesco De Rango ◽  
Paolina Crocco ◽  
Francesca Iannone ◽  
Adolfo Saiardi ◽  
Giuseppe Passarino ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Inositol Phosphates ◽  
Nutrient Sensing ◽  
Human Longevity ◽  
Cell Physiology ◽  
Inositol Polyphosphate ◽  
Moonlighting Protein ◽  
Key Enzyme ◽  
Female Longevity ◽  
Inositol Polyphosphate Multikinase

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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