A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex.

Background: Phospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP) from phosphatidylinositol 4,5-bisphosphate (PIP). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions.

The inositol phosphate signalling network in physiology and disease.

Combinatorial substitution of phosphate groups on the inositol ring gives rise to a plethora of inositol phosphates (InsPs) and inositol pyrophosphates (PP-InsPs). These small molecules constitute an elaborate metabolic and signalling network that influences nearly every cellular function. This review delves into the knowledge accumulated over the past decades regarding the biochemical principles and significance of InsP metabolism.

Extracellular Cleavage of Microglia-Derived Progranulin Promotes Diet-Induced Obesity.

Hypothalamic innate immune responses to dietary fats underpin the pathogenesis of obesity, in which microglia play a critical role. Progranulin (PGRN) is an evolutionarily conserved secretory protein containing seven and a half granulin (GRN) motifs. It is cleaved into GRNs by multiple proteases.

GIRK2 potassium channels expressed by the AgRP neurons decrease adiposity and body weight in mice.

It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function.

Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors.

Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis.

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain.

Acute stress response triggers various physiological responses such as energy mobilization to meet metabolic demands. However, the underlying molecular changes in the brain remain largely obscure. Here, we used a brief water avoidance stress (WAS) to elicit an acute stress response in mice.

Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress.

The chronic consumption of diets rich in saturated fats leads to obesity and associated metabolic disorders including diabetes and atherosclerosis. Intake of a high-fat diet (HFD) is also recognized to dysregulate neural functions such as cognition, mood, and behavior. However, the effects of short-term high-fat diets on the brain are elusive.

miRNA-Induced Downregulation of IPMK in Macrophages Mediates Lipopolysaccharide-Triggered TLR4 Signaling.

Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme responsible for the production of inositol polyphosphates and phosphoinositide. IPMK in macrophages was identified as a key factor for the full activation of the Toll-like receptor 4 (TLR4) signaling pathway and inflammation by directly interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6). Here, dynamic changes of IPMK levels in lipopolysaccharide (LPS)-stimulated macrophages and their functional significance were investigated.

Drug discovery inspired by bioactive small molecules from nature.

Natural products (NPs) have greatly contributed to the development of novel treatments for human diseases such as cancer, metabolic disorders, and infections. Compared to synthetic chemical compounds, primary and secondary metabolites from medicinal plants, fungi, microorganisms, and our bodies are promising resources with immense chemical diversity and favorable properties for drug development. In addition to the well-validated significance of secondary metabolites, endogenous small molecules derived from central metabolism and signaling events have shown great potential as drug candidates due to their unique metabolite-protein interactions.

Gut Epithelial Inositol Polyphosphate Multikinase Alleviates Experimental Colitis via Governing Tuft Cell Homeostasis.

Background & Aims: Inositol polyphosphate multikinase (IPMK), an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. Recent studies have identified single-nucleotide polymorphisms in the IPMK gene associated with inflammatory bowel disease predisposition. Therefore, we aimed to investigate the functional significance of IPMK in gut epithelium.

Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR.

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor.

Differentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca influx.

Activated Foxp3 regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)-mediated induction and regulation of store-operated Ca entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear.

Effect of Metal-Precursor Stacking Order on Volume-Defect Formation in CZTSSe Thin Film: Formation Mechanism of Blisters and Nanopores.

In this study, we investigated the effect of the stacking order of metal precursors on the formation of volume defects, such as blisters and nanopores, in CZTSSe thin-film solar cells. We fabricated CZTSSe thin films using three types of metal-precursor combinations, namely, Zn/Cu/Sn/Mo, Cu/Zn/Sn/Mo, and Sn/Cu/Zn/Mo, and studied the blister formation. The blister-formation mechanism was based on the delamination model, taking into consideration the compressive stress and adhesion properties.

Inositol polyphosphate multikinase physically binds to the SWI/SNF complex and modulates BRG1 occupancy in mouse embryonic stem cells.

Inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising the question of how IPMK contributes to transcriptional regulation in mammals.

Deletion of IP6K1 in mice accelerates tumor growth by dysregulating the tumor-immune microenvironment.

A family of inositol hexakisphosphate kinases (IP6Ks) catalyzes the production of inositol pyrophosphate IP (5-diphosphoinositolpentakisphosphate) which is known to modulate various biological events such as cell growth. While targeting IP6K1 in various cancer cells has been well reported to control cancer cell motility and invasiveness, the role of host IP6K1 in tumor progression remains unknown. By using a syngeneic MC38 murine mouse colon carcinoma model, here we examined how host IP6K1 in the tumor microenvironment influences tumor growth.

TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition.

Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (-(-trifluorobenzyl), -(-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms.

Myeloid IPMK promotes the resolution of serum transfer-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases.

Inositol Polyphosphate Multikinase Signaling: Multifaceted Functions in Health and Disease.

Inositol phosphates are water-soluble intracellular signaling molecules found in eukaryotes from yeasts to mammals, which are synthesized by a complex network of enzymes including inositol phosphate kinases. Among these, inositol polyphosphate multikinase (IPMK) is a promiscuous enzyme with broad substrate specificity, which phosphorylates multiple inositol phosphates, as well as phosphatidylinositol 4,5-bisphosphate. In addition to its catalytic actions, IPMK is known to non-catalytically control major signaling events via direct protein-protein interactions.

CZTSSe Formation Mechanism Using a Cu/Zn/SnS Stacked Precursor: Origin of Triple CZTSSe Layer Formation.

In this study, to control the formation of non-uniformly distributed large voids and Cu-Sn alloy agglomeration, which leads to local compositional misfit and secondary phase formation, a SnS compound precursor was applied instead of metal Sn to avoid compositional non-uniformity. Using a Cu/Zn/SnS stacked precursor, a temperature tracking experiment was conducted to confirm the formation controllability of the void and the secondary phase. According to the results of this temperature-profile tracking experiment, it was confirmed that the large void was successfully controlled; however, an additional ZnSSe secondary phase layer was formed in the middle of the CZTSSe upper layer and small voids were distributed relatively uniformly in the bottom CZTSSe layer.

Effect of AlO Dot Patterning on CZTSSe Solar Cell Characteristics.

In this study, a 5-nm thick AlO layer was patterned onto the Mo electrode in the form of a dot to produce a local rear contact, which looked at the effects of this contact structure on CuZnSn(SSe) (CZTSSe) growth and solar cell devices. Mo was partially exposed through open holes having a square dot shape, and the closed-ratios of AlO passivated areas were 56%, 75%, and 84%. The process of synthesizing CZTSSe is the same as that of the previous process showing 12.

Inositol polyphosphate multikinase in adipocytes is dispensable for regulating energy metabolism and whole body metabolic homeostasis.

Adipose tissue plays a central role in regulating whole body energy and glucose homeostasis at both organ and systemic levels. Inositol polyphosphates, such as 5-diphosphoinositol pentakisphosphate, reportedly control adipocyte functions and energy expenditure. However, the physiological roles of the inositol polyphosphate (IP) pathway in the adipose tissue are not yet fully defined.

GATA3 induces the upregulation of UCP-1 by directly binding to PGC-1α during adipose tissue browning.

Objective: Obesity is recognized as the cause of multiple metabolic diseases and is rapidly increasing worldwide. As obesity is due to an imbalance in energy homeostasis, the promotion of energy consumption through browning of white adipose tissue (WAT) has emerged as a promising therapeutic strategy to counter the obesity epidemic. However, the molecular mechanisms of the browning process are not well understood.

Inositol Pyrophosphates: Signaling Molecules with Pleiotropic Actions in Mammals.

Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP7) are inositol metabolites containing high-energy phosphoanhydride bonds. Biosynthesis of PP-IPs is mediated by IP6 kinases (IP6Ks) and PPIP5 kinases (PPIP5Ks), which transfer phosphate to inositol hexakisphosphate (IP6). Pleiotropic actions of PP-IPs are involved in many key biological processes, including growth, vesicular remodeling, and energy homeostasis.

Inositol hexakisphosphate kinase-1 is a key mediator of prepulse inhibition and short-term fear memory.

Inositol phosphate metabolism has emerged as one of the key players in synaptic transmission. Previous studies have shown that the deletion of inositol hexakisphosphate kinase 1 (IP6K1), which is responsible for inositol pyrophosphate biosynthesis, alters probability of presynaptic vesicle release and short-term facilitation of glutamatergic synapses in mouse hippocampus. However, the behavioral and cognitive functions regulated by IP6K1 remain largely elusive.

Inositol Pyrophosphate Metabolism Regulates Presynaptic Vesicle Cycling at Central Synapses.

The coordination of synaptic vesicle exocytosis and endocytosis supports neurotransmitter release from presynaptic terminals. Although inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (5-IP), are versatile signaling metabolites in many biological events, physiological actions of 5-IP on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP in synaptic transmission in hippocampal brain slices from inositol hexakisphosphate kinase 1 (Ip6k1)-knockout mice.