BBA - Molecular and Cell Biology of Lipids (v.1761, #5-6)

Lipid signaling in the nucleus by Daniel M. Raben (503-504).

The extent and content of this review issue highlights how our understanding of lipid signalling in the nucleus has grown, both in what we actually know, and the breadth of signalling pathways that we now have to consider. Here, a few key issues with regard to nuclear inositide signalling are briefly addressed.
Keywords: Inositol; Nucleus; Phosphatidylinositol 4,5-bisphosphate; Inositol hexakisphosphate; Inositol lipids; Nuclear envelope;

Phosphoinositide-specific phospholipase C (PI-PLC) β1 and nuclear lipid-dependent signaling by Lucio Cocco; Irene Faenza; Roberta Fiume; Anna Maria Billi; R. Stewart Gilmour; Francesco A. Manzoli (509-521).
Over the last years, evidence has suggested that phosphoinositides, which are involved in the regulation of a large variety of cellular processes both in the cytoplasm and in the plasma membrane, are present also within the nucleus. A number of advances has resulted in the discovery that phosphoinositide-specific phospholipase C signalling in the nucleus is involved in cell growth and differentiation. Remarkably, the nuclear inositide metabolism is regulated independently from that present elsewhere in the cell. Even though nuclear inositol lipids hydrolysis generates second messengers such as diacylglycerol and inositol 1,4,5-trisphosphate, it is becoming increasingly clear that in the nucleus polyphosphoinositides may act by themselves to influence pre-mRNA splicing and chromatin structure. Among phosphoinositide-specific phospholipase C, the β1 isoform appears to be one of the key players of the nuclear lipid signaling. This review aims at highlighting the most significant and up-dated findings about phosphoinositide-specific phospholipase C β1 in the nucleus.
Keywords: Phosphoinositide-specific phospholipase C; Nucleus; Signaling; Inositol lipid;

Coordinated intracellular translocation of phosphoinositide-specific phospholipase C-δ with the cell cycle by Hitoshi Yagisawa; Masashi Okada; Yoko Naito; Koh Sasaki; Masaki Yamaga; Makoto Fujii (522-534).
The δ family phosphoinositide (PI)-specific phospholipase C (PLC) are most fundamental forms of eukaryotic PI-PLCs. Despite the presence of lipid targeting domains such as the PH domain and C2 domain, the isoforms are also found in the cytoplasm and nucleus as well as at the plasma membrane. The isoforms have sequences or regions that can serve as a nuclear localization signal (NLS) and a nuclear export signal (NES). Their intracellular localization differs from one isoform to another, presumably due to the difference in the transport equilibrium balanced by the strength of the two signals of each isoform. Even for a particular isoform, its intracellular localization seems to vary during the cell cycle. As an example, PLCδ1, which is generally found at the plasma membrane and in the cytoplasm of quiescent cells, localizes to discrete nuclear structures in the G1/S boundary of the cell cycle. This may be at least partly due to an increase in intracellular Ca2+, since Ca2+ facilitates the formation of a nuclear transport complex comprised of PLCδ1 and importin β1, a carrier molecule for the nuclear import. PLCδ1 as well as PLCδ4 may play a pivotal role in controlling the initiation of DNA synthesis in S phase. Spatio-temporal changes in the levels of PtdIns(4,5)P2 seem to be another major determinant for the localization and regulation of the δ isoforms. High nuclear PtdIns(4,5)P2 levels are associated with the G1/S phases. After entering M phase, PtdIns(4,5)P2 synthesis at sites of cell division occurs and PLCs seem to localize to the cleavage furrow during cytokinesis. Coordinated translocation of PLCs with the cell cycle or with stress responses may result in changes in intra-nuclear environments and local membrane architectures that modulate proliferation and differentiation. In this review, recent findings regarding the molecular machineries and mechanisms of the nucleocytoplasmic shuttling as well as roles in the cell cycle progression of the δ isoforms of PLC will be discussed.
Keywords: Phospholipase C; Nucleocytoplasmic shuttling; NLS/NES; Importin; Intracellular Ca2+; Cleavage furrow;

There exists phosphoinositide (PI) cycle in the nucleus, which is operated differentially from the classical PI cycle at the plasma membrane. Evidence has been accumulated that nuclear PIs and the related enzymes are closely involved in a variety of nuclear processes, although the details remain to be elucidated. In this mini review, some components of PI cycle, i.e., diacylglycerol, phosphatidic acid, and the converting enzyme, diacylglycerol kinase, in the nucleus are discussed with focusing on the lipid metabolism, cell cycle regulation, and animal models.
Keywords: Phosphoinositide cycle; Diacylglycerol; Phosphatidic acid; Diacylgycerol kinase; Nucleus; Animal model;

Nuclear protein kinase C by Alberto M. Martelli; Camilla Evangelisti; Maria Nyakern; Francesco Antonio Manzoli (542-551).
Protein kinase C (PKC) isozymes constitute a family of ubiquitous phosphotransferases which act as key transducers in many agonist-induced signaling cascades. To date, at least 11 different PKC isotypes have been identified and are believed to play distinct regulatory roles. PKC isoforms are physiologically activated by a number of lipid cofactors. PKC is thought to reside in the cytoplasm in an inactive conformation and to translocate to the plasma membrane or cytoplasmic organelles upon cell activation by different stimuli. However, a sizable body of evidence collected over the last 20 years has shown PKC to be capable of translocating to the nucleus. Furthermore, PKC isoforms are resident within the nucleus. Studies from independent laboratories have to led to the identification of quite a few nuclear proteins which are PKC substrates and to the characterization of nuclear PKC-binding proteins which may be critical for finely tuning PKC function in this cell microenvironment. Several lines of evidence suggest that nuclear PKC isozymes are involved in the regulation of biological processes as important as cell proliferation and differentiation, gene expression, neoplastic transformation, and apoptosis. In this review, we shall highlight the most intriguing and updated findings about the functions of nuclear PKC isozymes.
Keywords: Nucleus; Protein kinase C; Signal transduction; Phosphorylation; Gene expression; Lipid second messengers;

Inositide signaling pathways represent a multifaceted ensemble of cellular switches capable of regulating a number of processes, for example, intracellular calcium release, membrane trafficking, chemotaxis, ion channel activity and several nuclear functions. Over 30 inositide messengers are found in eukaryotic cells that may be grouped into two classes: (1) inositol lipids, phosphatidylinositols or phosphoinositides (PIPs) and (2) water-soluble inositol polyphosphates (IPs). This review will focus on inositol polyphosphate kinases (IPK) and inositol pyrophosphate synthases (IPS) responsible for the cellular production of IP4, IP5 IP6 and PP-IPs. Of interest, IPK and IPS proteins localize, in part, within the nucleus and their activities are necessary for proper regulation of gene expression, mRNA export, DNA repair and telomere maintenance. The breadth of nuclear processes regulated and the evolutionary conservation of the genes involved in their synthesis have sparked renewed interest in inositide messengers derived from sequential phosphorylation of inositol 1,4,5-trisphosphate.
Keywords: Nuclear process; Inositol polyphosphate; Phosphorylation;

Nuclear PI(4,5)P2: A new place for an old signal by Matthew W. Bunce; Karen Bergendahl; Richard A. Anderson (560-569).
Over the last decades, evidence has accumulated suggesting that there is a distinct nuclear phosphatidylinositol pathway. One of the best examined nuclear lipid pathways is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI4,5P2) by PLC resulting in activation of nuclear PKC and production of inositol polyphosphates. However, there is a growing number of data that phosphoinositides are not only precursor for soluble inositol phosphates and diacylglycerol, instead they can act as second messengers themselves. They have been implicated to play a role in different important nuclear signaling events such as cell cycle progression, apoptosis, chromatin remodeling, transcriptional regulation and mRNA processing. This review focuses on the role of specifically PI4,5P2 in the nucleus as a second messenger as well as a precursor for PI3,4,5P3, inositol polyphosphates and diacylglycerol.
Keywords: Phosphatidylinositol 4,5-bisphopshate; Phospholipase C; Diacylglycerol; Cell cycle; Chromatin remodeling; Nuclear speckle;

The nuclear GTPase PIKE (PI 3-kinase Enhancer) binds PI 3-kinase and enhances it lipid kinase activity. PIKE predominantly distributes in the brain, and nerve growth factor stimulation triggers PIKE activation by provoking nuclear translocation of PLC-γ1, which acts as a physiologic guanine nucleotide exchange factor (GEF) for PIKE through its SH3 domain. PIKE contains GTPase and ArfGAP domains, which are separated by a PH domain. C-terminal ArfGAP domain activates its internal GTPase activity, and this process is regulated by the interaction between phosphatidylinositols and PH domain. PI 3-kinase occurs in the nuclei of a broad range of cell types, and various stimuli elicit its nuclear translocation. The nuclei from NGF-treated PC12 cells are resistant to DNA fragmentation initiated by activated cell-free apoptosome, for which PIKE/nuclear PI 3-kinase signaling through nuclear PI(3,4,5)P3 and Akt plays an essential role. As a nuclear receptor for PI(3,4,5)P3, B23 binds to PI(3,4,5)P3 in an NGF-dependent way. The PI(3,4,5)P3/B23 complex inhibits DNA fragmentation activity of CAD. Nuclear Akt regulation of apoptosis is dependent on its phosphorylation of key substrates in the nucleus, but the identities of these substrates are unknown. Identification of its nuclear substrates will further our understanding of the physiological roles of nuclear PI 3-kinase/Akt signaling.
Keywords: PIKE GTPase; PI 3-kinase; Phosphatidylinositol; Phosphorylation; Apoptosis;

Signal transductions via periodic generation and mobilisation of lipid second messengers within the nuclear matrix of eukaryotic cells have focused renewed attention on their precursor phospholipids' location, structure, form and function. The nuclear matrix contains and supports dynamic pools of phosphatidylcholine and phosphatidylinositol which serve as parent molecules of lipid second messengers but also of other phospholipids requiring cyclical replacement as cells proliferate. Applications of new, highly sensitive and specific analytical methodologies based on tandem electrospray ionisation mass spectrometry and the use of stable isotopes have allowed both static and dynamic lipidomic profiling of these endonuclear phospholipid pools. Together with more conventional enzymatic analyses and evaluation of the effect of specific “knock-out” of phospholipid transfer capacity, a number of important principles have been established. Specifically, a compartmental capacity to synthesise and remodel highly saturated phosphatidylcholine exists alongside transport mechanisms that facilitate the nuclear import of phosphatidylinositol and other phospholipids synthesised elsewhere within the cell. Subnuclear fractionation and the use of newly emerging techniques for sensitive lipidomic profiling of polyphosphoinositides, diacylglycerols and phosphatidate molecular species offer the potential for further significant advances in the near future.
Keywords: Nuclear phospholipid; Electrospray ionisation mass spectrometry; Stable isotope labelling; Phosphatidylcholine; Phosphatidylinositol; Lipidomic;

Sphingolipids of the nucleus and their role in nuclear signaling by Robert W. Ledeen; Gusheng Wu (588-598).
Sphingolipids have important signaling and regulatory roles in the nuclei of all vertebrate cells examined to date. Sphingomyelin (SM) is the most abundant of this group and occurs in the nuclear envelope (NE) as well as intranuclear sites. The primary product of SM metabolism is ceramide, whose release by nuclear sphingomyelinase triggers apoptosis and other metabolic changes in the nucleus. Further catabolism results in free fatty acid and sphingosine formation, the latter being capable of conversion to sphingosine phosphate by action of a specific nuclear kinase. Finally, glycosphingolipids such as gangliosides occur in the NE where GM1, one member of the gangliotetraose family, influences Ca2+ flux by activation of a Na+/Ca2+ exchanger located in the inner membrane of the NE. The tightly associated GM1/exchanger complex was shown to exert a cytoprotective role in neurons and other cell types, as absence of this nuclear complex rendered cells vulnerable to apoptosis. A striking example of this mode of Ca2+ regulation is the greatly enhanced seizure activity in knockout mice lacking gangliotetraose gangliosides, involving programmed cell death in the CA3 region of the hippocampus. In this model, Ca2+ homeostasis was restored most effectively with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na+/Ca2+ exchanger.
Keywords: Sphingolipid; Sphingomyelin; Sphingomyelinase; Ceramide; Sphingosine phosphate; Ganglioside; Nuclear calcium; Ganglioside GM1;

Cell signaling, the essential role of O-GlcNAc! by Natasha E. Zachara; Gerald W. Hart (599-617).
An increasing body of evidence points to a central regulatory role for glucose in mediating cellular processes and expands the role of glucose well beyond its traditional role(s) in energy metabolism. Recently, it has been recognized that one downstream effector produced from glucose is UDP-GlcNAc. Levels of UDP-GlcNAc, and the subsequent addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to Ser/Thr residues, is involved in regulating nuclear and cytoplasmic proteins in a manner analogous to protein phosphorylation. O-GlcNAc protein modification is essential for life in mammalian cells, highlighting the importance of this simple post-translational modification in basic cellular regulation. Recent research has highlighted key roles for O-GlcNAc serving as a nutrient sensor in regulating insulin signaling, the cell cycle, and calcium handling, as well as the cellular stress response.
Keywords: Metabolic sensor; Signal transduction; Cellular stress; Post-translational modification; O-GlcNAc;

Metabolism of arachidonic acid to eicosanoids within the nucleus by Ming Luo; Nicolas Flamand; Thomas G. Brock (618-625).
The eicosanoids are a diverse family of molecules that have powerful effects on cell function. They are best known as intercellular messengers, having autocrine and paracrine effects following their secretion from the cells that synthesize them. Many of the eicosanoids are produced from one polyunsaturated fatty acid, arachidonic acid. The diversity of possible products that can be synthesized from arachidonic acid is due, in part to the variety of enzymes that can act on it. Over the past 15 years, studies have placed many, but not all, of these enzymes at or inside the nucleus. In some cases, the nuclear import or export of arachidonic acid-processing enzymes is highly regulated. Furthermore, nuclear receptors that are activated by specific eicosanoids are known to exist. Taken together, these findings indicate that the enzymatic conversion of arachidonic acid to specific signaling molecules can occur in the nucleus, that it is regulated, and that the synthesized products may act within the nucleus. The objectives of this commentary are to review what is known about the metabolism of arachidonic acid to eicosanoids within the nucleus and to point to important areas for future discovery.
Keywords: Arachidonic acid; Leukotriene; Prostanoid; 5-lipoxygenase; Cyclooxygenase;

Smads mediate signal transduction by cytokines of the transforming growth factor-beta family. Recent data show that intrinsic and extrinsic proteins of the inner nuclear membrane affect the activities of Smads. MAN1, an integral protein of the inner nuclear membrane, binds to receptor-regulated Smads and antagonizes signaling by transforming growth factor-beta, activin and bone morphogenic protein. Lamins A and C, extrinsic intermediate filament proteins of the inner nuclear membrane that are mutated in several human diseases, appear to regulate phosphorylation of Smads. These data demonstrate that proteins within and associated with the inner nuclear membrane lipid bilayer regulate signal transduction pathways involved in numerous developmental, physiological and pathophysiological processes.
Keywords: Nuclear envelope; Inner nuclear membrane; MAN1; Lamin; Transforming growth factor-beta; Bone morphogenic protein;