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Journal of Integrative Plant Biology Sep 2018Phospholipids, including phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS) and... (Review)
Review
Phospholipids, including phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS) and phosphoinositides, have emerged as an important class of cellular messenger molecules in various cellular and physiological processes, of which PA attracts much attention of researchers. In addition to its effect on stimulating vesicle trafficking, many studies have demonstrated that PA plays a crucial role in various signaling pathways by binding target proteins and regulating their activity and subcellular localization. Here, we summarize the functional mechanisms and target proteins underlying PA-mediated regulation of cellular signaling, development, hormonal responses, and stress responses in plants.
Topics: Phosphatidic Acids; Phosphatidylethanolamines; Phosphatidylglycerols; Phosphatidylinositols; Phosphatidylserines; Plant Development
PubMed: 29660254
DOI: 10.1111/jipb.12655 -
Advances in Biological Regulation Jan 2018In cortical and hippocampal neurons of the mammalian brain, the synaptic vesicle cycle is a series of steps that tightly regulate exo- and endocytosis of vesicles. Many... (Review)
Review
In cortical and hippocampal neurons of the mammalian brain, the synaptic vesicle cycle is a series of steps that tightly regulate exo- and endocytosis of vesicles. Many proteins contribute to this regulation, but lipids have recently emerged as critical regulators as well. Of all the many lipid signaling molecules, phosphatidic acid is important to the physical processes of membrane fusion. Therefore, the lipid-metabolizing enzymes that produce phosphatidic acid are vital to the regulation of the cycle. Our lab is particularly interested in the potential regulatory mechanisms and neuronal roles of two phosphatidic acid-producing enzymes: diacylglycerol kinase theta (DGKθ) and phospholipase D (PLD). We recently discovered a regulatory role of DGKθ on evoked endocytosis (Goldschmidt et al., 2016). In addition to this enzyme, studies implicate PLD1 in neurotransmission, although its precise role is of some debate. Altogether, the production of phosphatidic acid by these enzymes offer an interesting and novel pathway for the regulation of the synaptic vesicle cycle.
Topics: Animals; Endocytosis; Humans; Lipid Metabolism; Neurons; Phosphatidic Acids; Phospholipase D; Synaptic Transmission; Synaptic Vesicles
PubMed: 28986032
DOI: 10.1016/j.jbior.2017.09.009 -
Journal of Neurochemistry Nov 2022Major depressive disorder (MDD) is a severe disease of unknown pathogenesis with a lifetime prevalence of ~10%. Therapy requires prolonged treatment that often fails. We...
Major depressive disorder (MDD) is a severe disease of unknown pathogenesis with a lifetime prevalence of ~10%. Therapy requires prolonged treatment that often fails. We have previously demonstrated that ceramide levels in the blood plasma of patients and in mice with experimental MDD are increased. Neutralization of blood plasma ceramide prevented experimental MDD in mice. Mechanistically, we demonstrated that blood plasma ceramide accumulated in endothelial cells of the hippocampus, inhibited phospholipase D (PLD) and thereby decreased phosphatidic acid in the hippocampus. Here, we demonstrate that phosphatidic acid binds to and controls the activity of phosphotyrosine phosphatase (PTP1B) in the hippocampus and thus determines tyrosine phosphorylation of a variety of cellular proteins including TrkB. Injection of PLD, phosphatidic acid, or inhibition of PTP1B abrogated MDD and normalized cellular tyrosine phosphorylation, including phosphorylation of TrkB and neurogenesis in the hippocampus. Most importantly, these treatments also rapidly normalized behavior of mice with experimental MDD. Since phosphatidic acid binds to and inhibits PTP1B, the lack of phosphatidic acid results in increased activity of PTP1B and thereby in reduced tyrosine phosphorylation of TrkB and other cellular proteins. Thus, our data indicate a novel pathogenetic mechanism of and a rapidly acting targeted treatment for MDD.
Topics: Mice; Animals; Phosphatidic Acids; Depressive Disorder, Major; Endothelial Cells; Phosphorylation; Ceramides; Tyrosine
PubMed: 36227646
DOI: 10.1111/jnc.15708 -
Molecules (Basel, Switzerland) Oct 2022The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease,... (Review)
Review
The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients' quality of life and medical expenses. Furthermore, there are limited drugs for treating diabetic nephropathy patients. Impaired lipid signaling, especially abnormal protein kinase C (PKC) activation by de novo-synthesized diacylglycerol (DG) under high blood glucose, is one of the causes of diabetic nephropathy. DG kinase (DGK) is an enzyme that phosphorylates DG and generates phosphatidic acid, i.e., DGK can inhibit PKC activation under diabetic conditions. Indeed, it has been proven that DGK activation ameliorates diabetic nephropathy. In this review, we summarize the involvement of PKC and DGK in diabetic nephropathy as therapeutic targets, and its mechanisms, by referring to our recent study.
Topics: Humans; Diacylglycerol Kinase; Diabetic Nephropathies; Diglycerides; Blood Glucose; Quality of Life; Phosphatidic Acids; Protein Kinase C; Diabetes Mellitus
PubMed: 36296376
DOI: 10.3390/molecules27206784 -
Autophagy Nov 2022Macroautophagy/autophagy is a finely-regulated process in which cytoplasm encapsulated within transient organelles termed autophagosomes is delivered to lysosomes or...
Phosphatidic acid suppresses autophagy through competitive inhibition by binding GAPC (glyceraldehyde-3-phosphate dehydrogenase) and PGK (phosphoglycerate kinase) proteins.
Macroautophagy/autophagy is a finely-regulated process in which cytoplasm encapsulated within transient organelles termed autophagosomes is delivered to lysosomes or vacuoles for degradation. Phospholipids, particularly phosphatidic acid (PA) that functions as a second messenger, play crucial and differential roles in autophagosome formation; however, the underlying mechanism remains largely unknown. Here we demonstrated that PA inhibits autophagy through competitive inhibition of the formation of ATG3 (autophagy-related)-ATG8e and ATG6-VPS34 (vacuolar protein sorting 34) complexes. PA bound to GAPC (glyceraldehyde-3-phosphate dehydrogenase) or PGK (phosphoglycerate kinase) and promoted their interaction with ATG3 or ATG6, which further attenuated the interactions of ATG3-ATG8e or ATG6-VPS34, respectively. Structural and mutational analyses revealed the mechanism of PA binding with GAPCs and PGK3, and that GAPCs or ATG8e competitively interacted with ATG3, and PGK3 or VPS34 competitively interacted with ATG6, at the same binding interface. These results elucidate the molecular mechanism of how PA inhibits autophagy through binding GAPC or PGK3 proteins and expand the understanding of the functional mode of PA, demonstrating the importance of phospholipids in plant autophagy and providing a new perspective for autophagy regulation by phospholipids. ATG: autophagy-related; BiFC: bimolecular fluorescence complementation; co-IP: co-immunoprecipitation; Con A: concanamycin A; ER: endoplasmic reticulum; EZ: elongation zone; FRET-FLIM: fluorescence resonance energy transfer with fluorescence lifetime imaging microscopy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GST: glutathione S-transferase; MDC: monodansylcadaverine; MZ: meristem zone; PA: phosphatidic acid; PAS: phagophore assembly site; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PGK3: phosphoglycerate kinase; PtdIns3K: phosphatidylinositol 3-kinase; PLD: phospholipase D; TEM: transmission electron microscopy; TOR: target of rapamycin; VPS34: vacuolar protein sorting 34; WT: wild type; Y2H: yeast two-hybrid.
Topics: Autophagy; Autophagy-Related Proteins; Glyceraldehyde-3-Phosphate Dehydrogenases; Lysosomes; Phosphatidic Acids; Phosphoglycerate Kinase; Ubiquitin-Conjugating Enzymes
PubMed: 35289711
DOI: 10.1080/15548627.2022.2046449 -
Plant Physiology and Biochemistry : PPB Aug 2022Phosphatidic acid (PA) has emerged as an important lipid signal during abiotic and biotic stress conditions such as drought, salinity, freezing, nutrient starvation,...
Phosphatidic acid (PA) has emerged as an important lipid signal during abiotic and biotic stress conditions such as drought, salinity, freezing, nutrient starvation, wounding and microbial elicitation. PA acts during stress responses primarily via binding and translocating target proteins or through modulating their activity. Owing to the importance of PA during stress signaling and developmental stages, it is imperative to identify PA interacting proteins and decipher their specific roles. In the present study, we have identified PA binding proteins from the leaves of Arabidopsis thaliana. Mass spectroscopy analysis led to the identification of 21 PA binding proteins with known roles in various cellular processes. One of the PA-binding proteins identified during this study, AtARGAH2, was further studied to unravel the role of PA interaction. Recombinant AtARGAH2 binding with immobilized PA on a solid support validated PA-AtARGAH2 binding invitro. PA binding to AtARGAH2 leads to the enhancement of arginase enzymatic activity in a dose dependent manner. Enzyme kinetics of recombinant AtARGAH2 demonstrated a lower K value in presence of PA, suggesting role of PA in efficient enzyme-substrate binding. This simple approach could systematically be applied to perform an inclusive study on lipid binding proteins to elucidate their role in physiology of plants.
Topics: Arabidopsis; Arabidopsis Proteins; Phosphatidic Acids; Phospholipase D; Plant Leaves; Stress, Physiological
PubMed: 35752016
DOI: 10.1016/j.plaphy.2022.06.018 -
Acta Biochimica Polonica 2018Phosphatidic acid (PA) is the simplest glycerophospholipid naturally occurring in living organisms, and even though its content among other cellular lipids is minor, it... (Review)
Review
Phosphatidic acid (PA) is the simplest glycerophospholipid naturally occurring in living organisms, and even though its content among other cellular lipids is minor, it is drawing more and more attention due to its multiple biological functions. PA is a precursor for other phospholipids, acts as a lipid second messenger and, due to its structural properties, is also a modulator of membrane shape. Although much is known about interaction of PA with its effectors, the molecular mechanisms remain unresolved to a large degree. Throughout many of the well-characterized PA cellular sensors, no conserved binding domain can be recognized. Moreover, not much is known about the cellular dynamics of PA and how it is distributed among subcellular compartments. Remarkably, PA can play distinct roles within each of these compartments. For example, in the nucleus it behaves as a mitogen, influencing gene expression regulation, and in the Golgi membrane it plays a role in membrane trafficking. Here, we discuss how a biophysical experimental approach enabled PA behavior to be described in the context of a lipid bilayer and to what extent various physicochemical conditions may modulate the functional properties of this lipid. Understanding these aspects would help to unravel specific mechanisms of PA-driven membrane transformations and protein recruitment and thus would lead to a clearer picture of the biological role of PA.
Topics: Cell Compartmentation; Cell Membrane; Lipid Bilayers; Phosphatidic Acids
PubMed: 29913482
DOI: 10.18388/abp.2018_2592 -
Placenta Mar 2024Placental phospholipid synthesis is critical for the expansion of the placental exchange surface area and for production of signaling molecules. Despite their...
INTRODUCTION
Placental phospholipid synthesis is critical for the expansion of the placental exchange surface area and for production of signaling molecules. Despite their importance, it is not yet established which enzymes involved in the de novo synthesis and remodeling of placental phospholipids are expressed and active in the human placenta.
METHODS
We identified phospholipid synthesis enzymes by immunoblotting in placental homogenates and immunofluorescence in placenta tissue sections. Primary human trophoblast (PHT) cells from term healthy placentas (n = 10) were cultured and exposed to C labeled fatty acids (16:0, 18:1 and 18:2 n-6, 22:6 n-3) for 2 and 24 h. Three phospholipid classes; phosphatidic acid, phosphatidylcholine, and lysophosphatidylcholine containing C fatty acids were quantified by Liquid Chromatography with tandem mass spectrometry (LC/MS-MS).
RESULTS
Acyl transferase and phospholipase enzymes were detected in human placenta homogenate and primarily expressed in the syncytiotrophoblast. Three representative C fatty acids (16:0, 18:1 and 18:2 n-6) were incorporated rapidly into phosphatidic acid in trophoblasts, but C labeled docosahexaenoic acid (DHA; 22:6 n-3) incorporation was not detected. C DHA was incorporated into phosphatidylcholine. Lysophosphatidylcholine containing all four C labeled fatty acids were found in high abundance.
CONCLUSIONS
Phospholipid synthesis and remodeling enzymes are present in the syncytiotrophoblast. C labeled fatty acids were rapidly incorporated into cellular phospholipids. C DHA was incorporated into phospholipids through the remodeling pathway rather than by de novo synthesis. These understudied pathways are highly active and critical for structure and function of the placenta.
Topics: Humans; Pregnancy; Female; Placenta; Phospholipids; Lysophosphatidylcholines; Fatty Acids; Phosphatidylcholines
PubMed: 38278000
DOI: 10.1016/j.placenta.2024.01.007 -
International Journal of Molecular... Mar 2022Cells sense a variety of extracellular signals balancing their metabolism and physiology according to changing growth conditions. Plasma membranes are the outermost... (Review)
Review
Cells sense a variety of extracellular signals balancing their metabolism and physiology according to changing growth conditions. Plasma membranes are the outermost informational barriers that render cells sensitive to regulatory inputs. Membranes are composed of different types of lipids that play not only structural but also informational roles. Hormones and other regulators are sensed by specific receptors leading to the activation of lipid metabolizing enzymes. These enzymes generate lipid second messengers. Among them, phosphatidic acid (PA) is a well-known intracellular messenger that regulates various cellular processes. This lipid affects the functional properties of cell membranes and binds to specific target proteins leading to either genomic (affecting transcriptome) or non-genomic responses. The subsequent biochemical, cellular and physiological reactions regulate plant growth, development and stress tolerance. In the present review, we focus on primary (genome-independent) signaling events triggered by rapid PA accumulation in plant cells and describe the functional role of PA in mediating response to hormones and hormone-like regulators. The contributions of individual lipid signaling enzymes to the formation of PA by specific stimuli are also discussed. We provide an overview of the current state of knowledge and future perspectives needed to decipher the mode of action of PA in the regulation of cell functions.
Topics: Hormones; Phosphatidic Acids; Phospholipase D; Plant Development; Plant Proteins; Plants; Proteins; Signal Transduction
PubMed: 35328648
DOI: 10.3390/ijms23063227 -
Biochimica Et Biophysica Acta.... Oct 2019Lipins are phosphatidic acid phosphatase enzymes whose cellular function in regulating lipid metabolism has been known for decades, particularly in metabolically active... (Review)
Review
Lipins are phosphatidic acid phosphatase enzymes whose cellular function in regulating lipid metabolism has been known for decades, particularly in metabolically active tissues such as adipose tissue or liver. In recent years evidence is accumulating for key regulatory roles of the lipin family in innate immune cells. Lipins may help regulate signaling through relevant immune receptors such as Toll-like receptors, and are also integral part of the cellular machinery for lipid storage in these cells, thereby modulating certain inflammatory processes. Mutations in genes that encode for members of this family produce autoinflammatory hereditary diseases or diseases with an important inflammatory component in humans. In this review we summarize recent findings on the role of lipins in cells of the innate immune system and in the onset and progress of inflammatory processes.
Topics: Animals; Diglycerides; Humans; Immunity, Innate; Inflammation; Macrophages; Phosphatidate Phosphatase; Phosphatidic Acids
PubMed: 31220616
DOI: 10.1016/j.bbalip.2019.06.003