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The FEBS Journal May 2024Phosphatidic acid (PA), the simplest phospholipid, acts as a key metabolic intermediate and second messenger that impacts diverse cellular and physiological processes... (Review)
Review
Phosphatidic acid (PA), the simplest phospholipid, acts as a key metabolic intermediate and second messenger that impacts diverse cellular and physiological processes across species ranging from microbes to plants and mammals. The cellular levels of PA dynamically change in response to stimuli, and multiple enzymatic reactions can mediate its production and degradation. PA acts as a signalling molecule and regulates various cellular processes via its effects on membrane tethering, enzymatic activities of target proteins, and vesicular trafficking. Because of its unique physicochemical properties compared to other phospholipids, PA has emerged as a class of new lipid mediators influencing membrane structure, dynamics, and protein interactions. This review summarizes the biosynthesis, dynamics, and cellular functions and properties of PA.
Topics: Phosphatidic Acids; Humans; Animals; Signal Transduction; Cell Membrane
PubMed: 37103336
DOI: 10.1111/febs.16809 -
Plant, Cell & Environment May 2016Lipids are one of the major components of biological membranes including the plasma membrane, which is the interface between the cell and the environment. It has become... (Review)
Review
Lipids are one of the major components of biological membranes including the plasma membrane, which is the interface between the cell and the environment. It has become clear that membrane lipids also serve as substrates for the generation of numerous signalling lipids such as phosphatidic acid, phosphoinositides, sphingolipids, lysophospholipids, oxylipins, N-acylethanolamines, free fatty acids and others. The enzymatic production and metabolism of these signalling molecules are tightly regulated and can rapidly be activated upon abiotic stress signals. Abiotic stress like water deficit and temperature stress triggers lipid-dependent signalling cascades, which control the expression of gene clusters and activate plant adaptation processes. Signalling lipids are able to recruit protein targets transiently to the membrane and thus affect conformation and activity of intracellular proteins and metabolites. In plants, knowledge is still scarce of lipid signalling targets and their physiological consequences. This review focuses on the generation of signalling lipids and their involvement in response to abiotic stress. We describe lipid-binding proteins in the context of changing environmental conditions and compare different approaches to determine lipid-protein interactions, crucial for deciphering the signalling cascades.
Topics: Lipid Metabolism; Phosphatidic Acids; Plant Proteins; Plants; Signal Transduction; Stress, Physiological
PubMed: 26510494
DOI: 10.1111/pce.12666 -
Trends in Biochemical Sciences Jun 2019In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are... (Review)
Review
In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are carried out through a series of stages that lead to the formation of SNARE complexes between cellular compartment membranes to trigger fusion. Although the protein catalysts of membrane fusion are well characterized, their response to their surrounding microenvironment, provided by the lipid composition of the membrane, remains to be fully understood. Membranes are composed of bulk lipids (e.g., phosphatidylcholine), as well as regulatory lipids that undergo constant modifications by kinases, phosphatases, and lipases. These lipids include phosphoinositides, diacylglycerol, phosphatidic acid, and cholesterol/ergosterol. Here we describe the roles of these lipids throughout the stages of yeast vacuole homotypic fusion.
Topics: Cholesterol; Ergosterol; Glycerides; Humans; Membrane Fusion; Phosphatidic Acids; Phosphatidylinositols; Vacuoles
PubMed: 30587414
DOI: 10.1016/j.tibs.2018.12.003 -
Advances in Biological Regulation Jan 2023In mammals, phospholipase D (PLD) enzymes involve 6 isoforms, of which only three have established lipase activity to produce the signaling lipid phosphatidic acid (PA).... (Review)
Review
In mammals, phospholipase D (PLD) enzymes involve 6 isoforms, of which only three have established lipase activity to produce the signaling lipid phosphatidic acid (PA). This phospholipase activity has been postulated to contribute to cancer progression for over three decades now, but the exact mechanisms involved have yet to be uncovered. Indeed, using various models, an altered PLD activity has been proposed altogether to increase cell survival rate, promote angiogenesis, boost rapamycin resistance, and favor metastasis. Although for some part, the molecular pathways by which this increase in PA is pro-oncogenic are partially known, the pleiotropic functions of PA make it quite difficult to distinguish which among these simple signaling pathways is responsible for each of these PLD facets. In this review, we will describe an additional potential contribution of PA generated by PLD1 and PLD2 in the biogenesis, secretion, and uptake of exosomes. Those extracellular vesicles are now viewed as membrane vehicles that carry informative molecules able to modify the fate of receiving cells at distance from the original tumor to favor homing of metastasis. The perspectives for a better understanding of these complex role of PLDs will be discussed.
Topics: Animals; Humans; Exosomes; Mammals; Neoplasms; Phosphatidic Acids; Phospholipase D; Protein Isoforms; Signal Transduction
PubMed: 36272918
DOI: 10.1016/j.jbior.2022.100924 -
The Plant Journal : For Cell and... Apr 2021Symbiotic rhizobium-legume interactions, such as root hair curling, rhizobial invasion, infection thread expansion, cell division and proliferation of nitrogen-fixing...
Symbiotic rhizobium-legume interactions, such as root hair curling, rhizobial invasion, infection thread expansion, cell division and proliferation of nitrogen-fixing bacteroids, and nodule formation, involve extensive membrane synthesis, lipid remodeling and cytoskeleton dynamics. However, little is known about these membrane-cytoskeleton interfaces and related genes. Here, we report the roles of a major root phospholipase D (PLD), PLDα1, and its enzymatic product, phosphatidic acid (PA), in rhizobium-root interaction and nodulation. PLDα1 was activated and the PA content transiently increased in roots after rhizobial infection. Levels of PLDα1 transcript and PA, as well as actin and tubulin cytoskeleton-related gene expression, changed markedly during root-rhizobium interactions and nodule development. Pre-treatment of the roots of soybean seedlings with n-butanol suppressed the generation of PLD-derived PA, the expression of early nodulation genes and nodule numbers. Overexpression or knockdown of GmPLDα1 resulted in changes in PA levels, glycerolipid profiles, nodule numbers, actin cytoskeleton dynamics, early nodulation gene expression and hormone levels upon rhizobial infection compared with GUS roots. The transcript levels of cytoskeleton-related genes, such as GmACTIN, GmTUBULIN, actin capping protein 1 (GmCP1) and microtubule-associating protein (GmMAP1), were modified in GmPLDα1-altered hairy roots compared with those of GUS roots. Phosphatidic acid physically bound to GmCP1 and GmMAP1, which could be related to cytoskeletal changes in rhizobium-infected GmPLDα1 mutant roots. These data suggest that PLDα1 and PA play important roles in soybean-rhizobium interaction and nodulation. The possible underlying mechanisms, including PLDα1- and PA-mediated lipid signaling, membrane remodeling, cytoskeleton dynamics and related hormone signaling, are discussed herein.
Topics: Gene Expression Regulation, Plant; Phosphatidic Acids; Phospholipase D; Plant Root Nodulation; Glycine max; Symbiosis
PubMed: 33377234
DOI: 10.1111/tpj.15152 -
Advances in Biological Regulation Jan 2019Fine-tuned regulation of new proteins synthesis is key to the fast adaptation of cells to their changing environment and their response to external cues. Protein... (Review)
Review
Fine-tuned regulation of new proteins synthesis is key to the fast adaptation of cells to their changing environment and their response to external cues. Protein synthesis regulation is particularly refined and important in the case of highly polarized cells like neurons where translation occurs in the subcellular dendritic compartment to produce long-lasting changes that enable the formation, strengthening and weakening of inter-neuronal connection, constituting synaptic plasticity. The changes in local synaptic proteome of neurons underlie several aspects of synaptic plasticity and new protein synthesis is necessary for long-term memory formation. Details of how neuronal translation is locally controlled only start to be unraveled. A generally accepted view is that mRNAs are transported in a repressed state and are translated locally upon externally cued triggering signaling cascades that derepress or activate translation machinery at specific sites. Some important yet poorly considered intermediates in these cascades of events are signaling lipids such as diacylglycerol and its balancing partner phosphatidic acid. A link between these signaling lipids and the most common inherited cause of intellectual disability, Fragile X syndrome, is emphasizing the important role of these secondary messages in synaptically controlled translation.
Topics: Animals; Diglycerides; Fragile X Syndrome; Humans; Neuronal Plasticity; Neurons; Phosphatidic Acids; Protein Biosynthesis; Signal Transduction; Synapses
PubMed: 30262213
DOI: 10.1016/j.jbior.2018.09.005 -
Critical Reviews in Biotechnology May 2023Lipids are widely distributed in various tissues of an organism, mainly in plant storage organs (e.g., fruits, seeds, etc.). Lipids are vital biological substances that... (Review)
Review
Lipids are widely distributed in various tissues of an organism, mainly in plant storage organs (e.g., fruits, seeds, etc.). Lipids are vital biological substances that are involved in: signal transduction, membrane biogenesis, energy storage, and the formation of transmembrane fat-soluble substances. Some lipids and related lipid derivatives could be changed in their: content, location, or physiological activity by the external environment, such as biotic or abiotic stresses. Lipid phosphate phosphatases (LPPs) play important roles in regulating intermediary lipid metabolism and cellular signal response. LPPs can dephosphorylate lipid phosphates containing phosphate monolipid bonds such as: phosphatidic acid, lysophosphatidic acid (LPA), and diacylglycerol pyrophosphate, etc. These processes can change the contents of some important lipid signal mediation such as diacylglycerol and LPA, affecting lipid signal transmission. Here, we summarize the research progress of LPPs in plants, emphasizing the structural and biochemical characteristics of LPPs and their role in spatio-temporal regulation. In the future, more in-depth studies are required to boost our understanding of the key role of plant LPPs and lipid metabolism in: signal regulation, stress tolerance pathway, and plant growth and development.
Topics: Phosphatidate Phosphatase; Signal Transduction; Phosphatidic Acids; Phosphates; Lipid Metabolism
PubMed: 35430946
DOI: 10.1080/07388551.2022.2032588 -
Arteriosclerosis, Thrombosis, and... Jun 2023AGK (acylglycerol kinase) was first identified as a mitochondrial transmembrane protein that exhibits a lipid kinase function. Recent studies have established that AGK...
BACKGROUND
AGK (acylglycerol kinase) was first identified as a mitochondrial transmembrane protein that exhibits a lipid kinase function. Recent studies have established that AGK promotes cancer growth and metastasis, enhances glycolytic metabolism and function fitness of CD8 T cells, or regulates megakaryocyte differentiation. However, the role of AGK in platelet activation and arterial thrombosis remains to be elaborated.
METHODS
We performed hematologic analysis using automated hematology analyzer and investigated platelets morphology by transmission electron microscope. We explored the role of AGK in platelet activation and arterial thrombosis utilizing transgenic mice, platelet functional experiments in vitro, and thrombosis models in vivo. We revealed the regulation effect of AGK on Talin-1 by coimmunoprecipitation, mass spectrometry, immunofluorescence, and Western blot. We tested the role of AGK on lipid synthesis of phosphatidic acid/lysophosphatidic acid and thrombin generation by specific Elisa kits.
RESULTS
In this study, we found that AGK depletion or AGK mutation had no effect on the platelet average volumes, the platelet microstructures, or the expression levels of the major platelet membrane receptors. However, AGK deficiency or AGK mutation conspicuously decreased multiple aspects of platelet activation, including agonists-induced platelet aggregation, granules secretion, JON/A binding, spreading on Fg (fibrinogen), and clot retraction. AGK deficiency or AGK mutation also obviously delayed arterial thrombus formation but had no effect on tail bleeding time and platelet procoagulant function. Mechanistic investigation revealed that AGK may promote Talin-1Ser425 phosphorylation and affect the αIIbβ3-mediated bidirectional signaling pathway. However, AGK does not affect lipid synthesis of phosphatidic acid/lysophosphatidic acid in platelets.
CONCLUSIONS
AGK, through its kinase activity, potentiates platelet activation and arterial thrombosis by promoting Talin-1 Ser425 phosphorylation and affecting the αIIbβ3-mediated bidirectional signaling pathway.
Topics: Animals; Mice; Blood Platelets; CD8-Positive T-Lymphocytes; Mice, Transgenic; Phosphatidic Acids; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Signal Transduction; Talin; Thrombosis
PubMed: 37051931
DOI: 10.1161/ATVBAHA.122.318647 -
Molecular Microbiology Jun 2020Although lipid signaling has been shown to serve crucial roles in mammals and plants, little is known about this process in filamentous fungi. Here we analyze the...
Although lipid signaling has been shown to serve crucial roles in mammals and plants, little is known about this process in filamentous fungi. Here we analyze the contribution of phospholipase D (PLD) and its product phosphatidic acid (PA) in hyphal morphogenesis and growth of Epichloë festucae and Neurospora crassa, and in the establishment of a symbiotic interaction between E. festucae and Lolium perenne. Growth of E. festucae and N. crassa PLD deletion strains in axenic culture, and for E. festucae in association with L. perenne, were analyzed by light-, confocal- and electron microscopy. Changes in PA distribution were analyzed in E. festucae using a PA biosensor and the impact of these changes on the endocytic recycling and superoxide production investigated. We found that E. festucae PldB, and the N. crassa ortholog, PLA-7, are required for polarized growth and cell fusion and contribute to ascospore development, whereas PldA/PLA-8 are dispensable for these functions. Exogenous addition of PA rescues the cell-fusion phenotype in E. festucae. PldB is also crucial for E. festucae to establish a symbiotic association with L. perenne. This study identifies a new component of the cell-cell communication and cell fusion signaling network for hyphal morphogenesis and growth of filamentous fungi.
Topics: Biosensing Techniques; Cell Communication; Cell Fusion; Epichloe; Gene Deletion; Gene Expression Regulation, Fungal; Hyphae; Lolium; Neurospora crassa; Phosphatidic Acids; Phosphatidylcholines; Phospholipase D; Signal Transduction; Spores, Fungal; Superoxides; Symbiosis
PubMed: 32022309
DOI: 10.1111/mmi.14480 -
Microvascular Research Jan 2022The lymphatic system plays important roles in various physiological and pathological phenomena. As a bioactive phospholipid, lysophosphatidic acid (LPA) has been... (Comparative Study)
Comparative Study
The lymphatic system plays important roles in various physiological and pathological phenomena. As a bioactive phospholipid, lysophosphatidic acid (LPA) has been reported to function as a lymphangiogenic factor as well as some growth factors, yet the involvement of phospholipids including LPA and its derivatives in lymphangiogenesis is not fully understood. In the present study, we have developed an in-vitro lymphangiogenesis model (termed a collagen sandwich model) by utilizing type-I collagen, which exists around the lymphatic endothelial cells of lymphatic capillaries in vivo. The collagen sandwich model has revealed that cyclic phosphatidic acid (cPA), and not LPA, augmented the tube formation of human dermal lymphatic endothelial cells (HDLECs). Both cPA and LPA increased the migration of HDLECs cultured on the collagen. As the gene expression of LPA receptor 6 (LPA) was predominantly expressed in HDLECs, a siRNA experiment against LPA attenuated the cPA-mediated tube formation. A synthetic LPA inhibitor, Ki16425, suppressed the cPA-augmented tube formation and migration of the HDLECs, and the LPA-induced migration. The activity of Rho-associated protein kinase (ROCK) located at the downstream of the LPA receptors was augmented in both the cPA- and LPA-treated cells. A potent ROCK inhibitor, Y-27632, suppressed the cPA-dependent tube formation but not the migration of the HDLECs. Furthermore, cPA, but not LPA, augmented the gene expression of VE-cadherin and β-catenin in the HDLECs. These results provide novel evidence that cPA facilitates the capillary-like morphogenesis and the migration of HDLECs through LPA/ROCK and LPA signaling pathways in concomitance with the augmentation of VE-cadherin and β-catenin expression. Thus, cPA is likely to be a potent lymphangiogenic factor for the initial lymphatics adjacent to type I collagen under physiological conditions.
Topics: Antigens, CD; Cadherins; Cell Movement; Cells, Cultured; Collagen Type I; Endothelial Cells; Humans; Lymphangiogenesis; Lymphatic Vessels; Lysophospholipids; Male; Phosphatidic Acids; Receptors, Lysophosphatidic Acid; Signal Transduction; beta Catenin; rho-Associated Kinases
PubMed: 34699844
DOI: 10.1016/j.mvr.2021.104273