The Inositol Phosphate System—A Coordinator of Metabolic Adaptability

All cells rely on nutrients to supply energy and carbon building blocks to support cellular processes. Over time, eukaryotes have developed increasingly complex systems to integrate information about available nutrients with the internal state of energy stores to activate the necessary processes to meet the immediate and ongoing needs of the cell. One such system is the network of soluble and membrane-associated inositol phosphates that coordinate the cellular responses to nutrient uptake and utilization from growth factor signaling to energy homeostasis. In this review, we discuss the coordinated interactions of the inositol polyphosphates, inositol pyrophosphates, and phosphoinositides in major metabolic signaling pathways to illustrate the central importance of the inositol phosphate signaling network in nutrient responses

Decoupling Bulk Thermodynamics and Wetting Characteristics of Block Copolymer Thin Films

The consequences on certain physical properties of controlled levels of epoxidation of the poly­(isoprene) blocks in poly­(styrene-<i>b</i>-isoprene) (PS-PI) diblock copolymers and poly­(isoprene) (hPI) homopolymers have been studied, where the products after epoxidation are denoted PS-PIxn and hPIxn, respectively. The effective interaction parameters χ_eff between the PS and the PIxn blocks were estimated by applying mean-field theory to the lamellar periodicities identified by small-angle X-ray scattering and to the order-to-disorder transition temperatures determined by dynamic mechanical spectroscopy. These results were fit to a binary segment–segment interaction parameter model indicating a nonlinear change in χ_eff with percent epoxidation. In contrast, contact angle measurement on hPIxn and lamellar orientations of thin-film PS-PIxn suggest that the surface energy of PIxn increases linearly with epoxidation. This decoupling of bulk and thin-film thermodynamic behaviors is attributed to the different roles that a random copolymer architecture plays in establishing three-dimensional order versus wetting at a two-dimensional surface

Directed Assembly of Lamellae Forming Block Copolymer Thin Films near the Order–Disorder Transition

The impact of thin film confinement on the ordering of lamellae was investigated using symmetric poly­(styrene-<i>b</i>-[isoprene-<i>ran</i>-epoxyisoprene]) diblock copolymers bound by nonpreferential wetting interfaces. The order–disorder transition temperature (<i>T</i>_ODT) and the occurrence of composition fluctuations in the disordered state are not significantly affected by two-dimensional confinement. Directed self-assembly using chemical patterning is demonstrated near <i>T</i>_ODT. These results establish the minimum feature size attainable using directed self-assembly of a given diblock copolymer system

Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3

<div><p>Imbalance of lipid metabolism has been linked with pathogenesis of a variety of human pathological conditions such as diabetes, obesity, cancer and neurodegeneration. Sterol regulatory element binding proteins (SREBPs) are the master transcription factors controlling the homeostasis of fatty acids and cholesterol in the body. Transcription, expression, and activity of SREBPs are regulated by various nutritional, hormonal or stressful stimuli, yet the molecular and cellular mechanisms involved in these adaptative responses remains elusive. In the present study, we found that overexpressed acyl-CoA binding domain containing 3 (ACBD3), a Golgi-associated protein, dramatically inhibited SREBP1-sensitive promoter activity of fatty acid synthase (FASN). Moreover, lipid deprivation-stimulated SREBP1 maturation was significantly attenuated by ACBD3. With cell fractionation, gene knockdown and immunoprecipitation assays, it was showed that ACBD3 blocked intracellular maturation of SREBP1 probably through directly binding with the lipid regulator rather than disrupted SREBP1-SCAP-Insig1 interaction. Further investigation revealed that acyl-CoA domain-containing N-terminal sequence of ACBD3 contributed to its inhibitory effects on the production of nuclear SREBP1. In addition, mRNA and protein levels of FASN and de novo palmitate biosynthesis were remarkably reduced in cells overexpressed with ACBD3. These findings suggest that ACBD3 plays an essential role in maintaining lipid homeostasis via regulating SREBP1's processing pathway and thus impacting cellular lipogenesis.</p> </div

Inositol polyphosphate multikinase modulates redox signaling through nuclear factor erythroid 2-related factor 2 and glutathione metabolism

Summary: Maintenance of redox balance plays central roles in a plethora of signaling processes. Although physiological levels of reactive oxygen and nitrogen species are crucial for functioning of certain signaling pathways, excessive production of free radicals and oxidants can damage cell components. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade is the key pathway that mediates cellular response to oxidative stress. It is controlled at multiple levels, which serve to maintain redox homeostasis within cells. We show here that inositol polyphosphate multikinase (IPMK) is a modulator of Nrf2 signaling. IPMK binds Nrf2 and attenuates activation and expression of Nrf2 target genes. Furthermore, depletion of IPMK leads to elevated glutathione and cysteine levels, resulting in increased resistance to oxidants. Accordingly, targeting IPMK may restore redox balance under conditions of cysteine and glutathione insufficiency