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Nature Chemical Biology Jul 2010Phosphoinositide (PI) lipids are essential components of eukaryotic cell membranes. They are produced by mono-, bis- and trisphosphorylation of the inositol headgroup of... (Review)
Review
Phosphoinositide (PI) lipids are essential components of eukaryotic cell membranes. They are produced by mono-, bis- and trisphosphorylation of the inositol headgroup of phosphatidylinositol (PtdIns) and are concentrated in separate pools of cytosolic membranes. PIs serve as markers of the cell compartments and form unique docking sites for protein effectors. Collectively, seven known PIs, the protein effectors that bind them and enzymes that generate or modify PIs compose a remarkably complex protein-lipid signaling network. A number of cytosolic proteins contain one or several effector modules capable of recognizing individual PIs and recruiting the host proteins to distinct intracellular compartment. The recently determined atomic-resolution structures and membrane-targeting mechanisms of a dozen PI effectors have provided insights into the molecular basis for regulation of endocytic membrane trafficking and signaling. In this review, I highlight the structural aspects of the deciphering of the 'PI code' by the most common PI-recognizing effectors and discuss the mechanistic details of their membrane anchoring.
Topics: Gene Expression Regulation; Models, Molecular; Phosphatidylinositols; Protein Structure, Tertiary
PubMed: 20559318
DOI: 10.1038/nchembio.390 -
BMB Reports Jul 2014Lipid components in biological membranes are essential for maintaining cellular function. Phosphoinositides, the phosphorylated derivatives of phosphatidylinositol (PI),... (Review)
Review
Lipid components in biological membranes are essential for maintaining cellular function. Phosphoinositides, the phosphorylated derivatives of phosphatidylinositol (PI), regulate many critical cell processes involving membrane signaling, trafficking, and reorganization. Multiple metabolic pathways including phosphoinositide kinases and phosphatases and phospholipases tightly control spatio-temporal concentration of membrane phosphoinositides. Metabolizing enzymes responsible for PI 4,5-bisphosphate (PI(4,5)P2) production or degradation play a regulatory role in Toll-like receptor (TLR) signaling and trafficking. These enzymes include PI 4-phosphate 5-kinase, phosphatase and tensin homolog, PI 3-kinase, and phospholipase C. PI(4,5)P2 mediates the interaction with target cytosolic proteins to induce their membrane translocation, regulate vesicular trafficking, and serve as a precursor for other signaling lipids. TLR activation is important for the innate immune response and is implicated in diverse pathophysiological disorders. TLR signaling is controlled by specific interactions with distinct signaling and sorting adaptors. Importantly, TLR signaling machinery is differentially formed depending on a specific membrane compartment during signaling cascades. Although detailed mechanisms remain to be fully clarified, phosphoinositide metabolism is promising for a better understanding of such spatio-temporal regulation of TLR signaling and trafficking.
Topics: Humans; Membrane Glycoproteins; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipases; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptors
PubMed: 24856829
DOI: 10.5483/bmbrep.2014.47.7.088 -
International Journal of Biological... 2020Phosphoinositides are membrane lipids generated by phosphorylation on the inositol head group of phosphatidylinositol. By specifically distributed to distinct... (Review)
Review
Phosphoinositides are membrane lipids generated by phosphorylation on the inositol head group of phosphatidylinositol. By specifically distributed to distinct subcellular membrane locations, different phosphoinositide species play diverse roles in modulating membrane trafficking. Among the seven known phosphoinositide species, phosphatidylinositol 4,5-bisphosphate (PI4,5P) is the one species most abundant at the plasma membrane. Thus, the PI4,5P function in membrane trafficking is first identified in controlling plasma membrane dynamic-related events including endocytosis and exocytosis. However, recent studies indicate that PI4,5P is also critical in many other membrane trafficking events such as endosomal trafficking, hydrolases sorting to lysosomes, autophagy initiation, and autophagic lysosome reformation. These findings suggest that the role of PI4,5P in membrane trafficking is far beyond just plasma membrane. This review will provide a concise synopsis of how PI4,5P functions in multiple membrane trafficking events. PI4,5P, the enzymes responsible for PI4,5P production at specific subcellular locations, and distinct PI4,5P effector proteins compose a regulation network to control the specific membrane trafficking events.
Topics: Cell Membrane; Cell Movement; Endocytosis; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols
PubMed: 33061794
DOI: 10.7150/ijbs.49665 -
Traffic (Copenhagen, Denmark) Feb 2020Among the structural phospholipids that form the bulk of eukaryotic cell membranes, phosphatidylinositol (PtdIns) is unique in that it also serves as the common... (Review)
Review
Among the structural phospholipids that form the bulk of eukaryotic cell membranes, phosphatidylinositol (PtdIns) is unique in that it also serves as the common precursor for low-abundance regulatory lipids, collectively referred to as polyphosphoinositides (PPIn). The metabolic turnover of PPIn species has received immense attention because of the essential functions of these lipids as universal regulators of membrane biology and their dysregulation in numerous human pathologies. The diverse functions of PPIn lipids occur, in part, by orchestrating the spatial organization and conformational dynamics of peripheral or integral membrane proteins within defined subcellular compartments. The emerging role of stable contact sites between adjacent membranes as specialized platforms for the coordinate control of ion exchange, cytoskeletal dynamics, and lipid transport has also revealed important new roles for PPIn species. In this review, we highlight the importance of membrane contact sites formed between the endoplasmic reticulum (ER) and plasma membrane (PM) for the integrated regulation of PPIn metabolism within the PM. Special emphasis will be placed on non-vesicular lipid transport during control of the PtdIns biosynthetic cycle as well as toward balancing the turnover of the signaling PPIn species that define PM identity.
Topics: Biological Transport; Cell Membrane; Endoplasmic Reticulum; Humans; Phosphatidylinositol Phosphates; Phosphatidylinositols
PubMed: 31650663
DOI: 10.1111/tra.12709 -
Biochemical Society Transactions Oct 2019The phosphoinositide (PIPn) family of signalling phospholipids are central regulators in membrane cell biology. Their varied functions are based on the phosphorylation... (Review)
Review
The phosphoinositide (PIPn) family of signalling phospholipids are central regulators in membrane cell biology. Their varied functions are based on the phosphorylation pattern of their inositol ring, which can be recognized by selective binding domains in their effector proteins and be modified by a series of specific PIPn kinases and phosphatases, which control their interconversion in a spatial and temporal manner. Yet, a unique feature of PIPns remains largely unexplored: their unusually uniform acyl chain composition. Indeed, while most phospholipids present a range of molecular species comprising acyl chains of diverse length and saturation, PIPns in several organisms and tissues show the predominance of a single hydrophobic backbone, which in mammals is composed of arachidonoyl and stearoyl chains. Despite evolution having favoured this specific PIPn configuration, little is known regarding the mechanisms and functions behind it. In this review, we explore the metabolic pathways that could control the acyl chain composition of PIPns as well as the potential roles of this selective enrichment. While our understanding of this phenomenon has been constrained largely by the technical limitations in the methods traditionally employed in the PIPn field, we believe that the latest developments in PIPn analysis should shed light onto this old question.
Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Binding Sites; Phosphatidylinositols; Signal Transduction
PubMed: 31657437
DOI: 10.1042/BST20190205 -
Biological & Pharmaceutical Bulletin Sep 2007Phosphoinositides are a family of phosphorylated derivatives of the membrane lipid phosphatidylinositol. These lipids are highly concentrated in distinct pools located... (Review)
Review
Phosphoinositides are a family of phosphorylated derivatives of the membrane lipid phosphatidylinositol. These lipids are highly concentrated in distinct pools located in a cell's plasma membrane, endosomes or nucleus, where they function as ligands for phosphoinositide-binding proteins. Protein domains that bind phosphoinositides include the pleckstrin homology (PH) domain, the phox homology (PX) domain and the Fab1p-YOPB-Vps27p-EEA1 (FYVE) domain. These domains are found in many proteins involved in intracellular signaling, membrane trafficking and cytoskeletal rearrangement. Recent studies have identified potential links between alterations to various signaling pathways involving phosphoinositides and the etiology of many human diseases.
Topics: Animals; Blood Proteins; Humans; Phosphatidylinositols; Phosphoproteins; Signal Transduction
PubMed: 17827706
DOI: 10.1248/bpb.30.1599 -
Cellular Physiology and Biochemistry :... 2014The present study was conducted to understand biochemical and biological characteristics of the phosphatidylinositol (PI) derivative...
BACKGROUND/AIMS
The present study was conducted to understand biochemical and biological characteristics of the phosphatidylinositol (PI) derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-Sn-glycero-3-phosphatidyl-D-1-inositol (diDCP-LA-PI) and its enantiomer 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-Sn-glycero-3-phosphatidyl-L-1-inositol (diDCP-LA-PIe), with 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) on the α and β position.
METHODS
Activities of protein kinase C (PKC) and protein phosphatases such as protein phosphatase 1 (PP1), PP2A, and protein tyrosine phosphatase 1B (PTP1B) were assayed under the cell-free conditions and in PC-12 cells. Akt1/2 activity was monitored by quantifying phosphorylation at Thr308/309 and Ser473/474 in PC-12 cells.
RESULTS
diDCP-LA-PI significantly activated PKCα, -βΙ, -δ, and -ε, to an extent greater than that for diDCP-LA-PIe. diDCP-LA-PI still activated PKC in PC-12 cells, with the potential higher than that for diDCP-LA-PIe. Both diDCP-LA-PI and diDCP-LA-PIe reduced PP1 activity to a similar extent (30% of basal levels). diDCP-LA-PI enhanced PP2A activity to 180% of basal levels, while diDCP-LA-PIe had no effect. Drastic inhibition of PTP1B was obtained with diDCP-LA-PI and diDCP-LA-PIe, the extent reaching nearly 0% of basal levels. diDCP-LA-PI and diDCP-LA-PIe increased phosphorylation of Akt1/2 at Thr308/309 and Ser473/474 in PC-12 cells in the presence and absence of the PP2A inhibitor okadaic acid, respectively.
CONCLUSION
The results of the present study show that diDCP-LA-PI and diDCP-LA-PIe exhibit different bioactivities with the different potentials each other.
Topics: Animals; PC12 Cells; Phosphatidylinositols; Phosphoprotein Phosphatases; Phosphorylation; Protein Kinases; Rats
PubMed: 24525749
DOI: 10.1159/000356670 -
Nature Reviews. Molecular Cell Biology Feb 2014
Topics: Animals; Carrier Proteins; Cell Membrane; Endoplasmic Reticulum; Ergosterol; Golgi Apparatus; Homeostasis; Humans; Lipid Bilayers; Lipid Metabolism; Membrane Proteins; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipid Transfer Proteins; Receptors, Steroid; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vitamin E Deficiency
PubMed: 24434885
DOI: 10.1038/nrm3740 -
Viruses Oct 2020Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such... (Review)
Review
Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.
Topics: Animals; Caenorhabditis elegans Proteins; Humans; Organelles; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Virus Diseases; Virus Replication; Viruses
PubMed: 33022924
DOI: 10.3390/v12101124 -
Biomolecules Mar 2019Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide... (Review)
Review
Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide range of intracellular processes, which include signal transduction and vesicular trafficking. In spite of the extensive knowledge on class I PI3Ks, recent advances in the study of the three class II PI3Ks (PIK3C2A, PIK3C2B and PIK3C2G) reveal their distinct and non-overlapping cellular roles and localizations. By finely tuning membrane lipid composition in time and space among different cellular compartments, this class of enzymes controls many cellular processes, such as proliferation, survival and migration. This review focuses on the recent developments regarding the coordination of membrane trafficking and intracellular signaling of class II PI3Ks through the confined phosphorylation of inositol phospholipids.
Topics: Animals; Cell Membrane; Humans; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphorylation; Protein Transport; Signal Transduction
PubMed: 30884740
DOI: 10.3390/biom9030104