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Physiological Reviews Jul 2013Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained... (Review)
Review
Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.
Topics: Animals; Cell Communication; Gene Expression Regulation; Molecular Structure; Phosphatidylinositols
PubMed: 23899561
DOI: 10.1152/physrev.00028.2012 -
Nature Immunology Mar 2023How lipidome changes support CD8 effector T (T) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated...
How lipidome changes support CD8 effector T (T) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIP with 3-4 double bonds), T cells have unique PIP marked by saturated fatty acyl chains (0-2 double bonds). PIP are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP) exclusively supported signaling immediately upon T cell antigen receptor activation. In late T cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP into downstream mediators, waned, and saturated PIP became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIP impaired T cell fitness and function, even in cells with abundant polyunsaturated PIP. Glucose was the substrate for de novo PIP synthesis, and was rapidly utilized for saturated PIP generation. Thus, separate PIP pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
Topics: Phosphatidylinositols; Phosphatidylinositol Phosphates; Signal Transduction; Type C Phospholipases; CD8-Positive T-Lymphocytes
PubMed: 36732424
DOI: 10.1038/s41590-023-01419-y -
Cells Dec 2022The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically... (Review)
Review
The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically distributed between the outer and inner leaflets. Additionally, the spatial distribution and organization of these lipids dramatically change in response to various cellular states, such as cell division, differentiation, and apoptosis. Division of one cell into two daughter cells is one of the most fundamental requirements for the sustenance of growth in all living organisms. The successful completion of cytokinesis, the final stage of cell division, is critically dependent on the spatial distribution and organization of specific lipids. In this review, we discuss the properties of various lipid species associated with cytokinesis and the mechanisms involved in their polarization, including forward trafficking, endocytic recycling, local synthesis, and cortical flow models. The differences in lipid species requirements and distribution in mitotic vs. male meiotic cells will be discussed. We will concentrate on sphingolipids and phosphatidylinositols because their transbilayer organization and movement may be linked via the cytoskeleton and thus critically regulate various steps of cytokinesis.
Topics: Male; Humans; Cytokinesis; Cell Division; Cell Membrane; Biological Transport; Phosphatidylinositols
PubMed: 36552741
DOI: 10.3390/cells11243977 -
International Journal of Molecular... Apr 2023Phafins are PH (Pleckstrin Homology) and FYVE (Fab1, YOTB, Vac1, and EEA1) domain-containing proteins. The Phafin protein family is classified into two groups based on... (Review)
Review
Phafins are PH (Pleckstrin Homology) and FYVE (Fab1, YOTB, Vac1, and EEA1) domain-containing proteins. The Phafin protein family is classified into two groups based on their sequence homology and functional similarity: Phafin1 and Phafin2. This protein family is unique because both the PH and FYVE domains bind to phosphatidylinositol 3-phosphate [PtdIns(3)P], a phosphoinositide primarily found in endosomal and lysosomal membranes. Phafin proteins act as PtdIns(3)P effectors in apoptosis, endocytic cargo trafficking, and autophagy. Additionally, Phafin2 is recruited to macropinocytic compartments through coincidence detection of PtdIns(3)P and PtdIns(4)P. Membrane-associated Phafins serve as adaptor proteins that recruit other binding partners. In addition to the phosphoinositide-binding domains, Phafin proteins present a poly aspartic acid motif that regulates membrane binding specificity. In this review, we summarize the involvement of Phafins in several cellular pathways and their potential physiological functions while highlighting the similarities and differences between Phafin1 and Phafin2. Besides, we discuss research perspectives for Phafins.
Topics: Carrier Proteins; Phosphatidylinositols; Phosphatidylinositol Phosphates; Intracellular Membranes; Apoptosis; Endosomes; Protein Binding
PubMed: 37175801
DOI: 10.3390/ijms24098096 -
Nature Communications Jul 2022Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo...
Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis.
Topics: Carcinogenesis; Humans; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Receptors, Steroid; T-Lymphocytes
PubMed: 35906240
DOI: 10.1038/s41467-022-32104-7 -
Cell Reports Sep 2023Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially...
Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.
Topics: Cell Line; Fatty Acids, Unsaturated; Ferroptosis; Phosphatidylinositols; Phospholipids; Humans
PubMed: 37691145
DOI: 10.1016/j.celrep.2023.113023 -
Journal of Lipid Research 2021The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (also known as phosphatidylinositol phosphates or PIPs) are... (Review)
Review
The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (also known as phosphatidylinositol phosphates or PIPs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind phosphoinositides and are recruited to cell membranes. Through the activities of phosphoinositide kinases and phosphoinositide phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule, phosphatidylinositol. PIP signals regulate a wide range of cellular functions, including cytoskeletal assembly, membrane budding and fusion, ciliogenesis, vesicular transport, and signal transduction. Given the many excellent reviews on phosphoinositide kinases, phosphoinositide phosphatases, and PIPs in general, in this review, we discuss recent studies and advances in PIP lipid signaling in the retina. We specifically focus on PIP lipids from vertebrate (e.g., bovine, rat, mouse, toad, and zebrafish) and invertebrate (e.g., Drosophila, horseshoe crab, and squid) retinas. We also discuss the importance of PIPs revealed from animal models and human diseases, and methods to study PIP levels both in vitro and in vivo. We propose that future studies should investigate the function and mechanism of activation of PIP-modifying enzymes/phosphatases and further unravel PIP regulation and function in the different cell types of the retina.
Topics: Phosphatidylinositols
PubMed: 32540927
DOI: 10.1194/jlr.TR120000806 -
Sub-cellular Biochemistry 2022The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions...
The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions between those stages. Each stage in the process is regulated by variously phosphorylated derivatives of phosphatidylinositol (PtdIns) which reside in the cytoplasmic face of the membrane lipid bilayer. PtdIns derivatives phosphorylated at the 3' position of the inositol moiety, called 3' phosphoinositides (3'PIs), regulate different stages of the sequence. 3'PIs are synthesized by numerous phosphoinositide 3'-kinases (PI3K) and other lipid kinases and phosphatases, which are themselves regulated by small GTPases of the Ras superfamily. The combined actions of these enzymes localize four principal species of 3'PI to distinct domains of the plasma membrane or to discrete organelles, with distinct biochemical activities confined to those domains. Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P) and phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P) regulate the early stages of macropinosome formation, which include cell surface ruffling and constrictions of circular ruffles which close into macropinosomes. Phosphatidylinositol 3-phosphate (PtdIns3P) regulates macropinosome fusion with other macropinosomes and early endocytic organelles. Phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P) mediates macropinosome maturation and shrinkage, through loss of ions and water, and subsequent traffic to lysosomes. The different characteristic rates of macropinocytosis in different cell types indicate levels of regulation which may be governed by the cell's capacity to generate 3'PIs.
Topics: Cell Membrane; Endosomes; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Pinocytosis
PubMed: 35378706
DOI: 10.1007/978-3-030-94004-1_7 -
Biomolecules Jun 2023Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low... (Review)
Review
Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus.
Topics: Phosphatidylinositols; Cell Nucleus; Phosphatidylinositol Phosphates; Cell Nucleolus; Nuclear Envelope
PubMed: 37509085
DOI: 10.3390/biom13071049 -
Production and Purification of Phosphatidylinositol Mannosides from Mycobacterium smegmatis Biomass.Current Protocols Jun 2022Mycobacterium tuberculosis, the etiological agent of tuberculosis, is regarded as the most successful pathogen of humankind and a major threat to global health. The...
Mycobacterium tuberculosis, the etiological agent of tuberculosis, is regarded as the most successful pathogen of humankind and a major threat to global health. The mycobacterial cell wall is vital for cell growth, virulence, and resistance to antibiotics, and thus constitutes a unique target for drug development. To characterize the enzymes catalyzing the synthesis of the cell wall components, considerable amounts of substrates are required. Since many mycobacterial cell wall lipids, particularly phosphatidylinositol mannosides (PIMs), are not commercially available, isolation from cell biomass is the most straightforward way to obtain these compounds. In this study, we optimized a protocol to extract and purify PIM species, in particular Ac PIM and Ac PIM , which can be further used for the identification and characterization of target enzymes. PIMs were extracted from Mycobacterium smegmatis mc 155 ΔPimE using organic solvents, and purified through three consecutive chromatography steps. Thin-layer chromatography (TLC) was used in-between purification steps to evaluate the success of lipid separation, and nuclear magnetic resonance (NMR) was used for product quantification and to assess purity. Typically, from a 60 g batch of M. smegmatis biomass we were able to isolate approximately 9 mg of Ac PIM and 1.8 mg of Ac PIM . This is the first time the purification of phosphatidylinositol tetramannoside has been reported. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Growth of M. smegmatis mc 155 ∆PimE Basic Protocol 2: Extraction of lipids from M. smegmatis mc 155 ∆PimE Basic Protocol 3: Treatment of the lipid extract for isolation of phospholipids Basic Protocol 4: Isolation of phosphatidylinositol mannosides Basic Protocol 5: Quantification of phosphatidylinositol mannosides.
Topics: Biomass; Chromatography, Thin Layer; Mannosides; Mycobacterium smegmatis; Mycobacterium tuberculosis; Phosphatidylinositols
PubMed: 35758621
DOI: 10.1002/cpz1.458