-
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 -
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 -
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 -
Current Opinion in Plant Biology Jun 2023Plants have developed fine-tuned cellular mechanisms to respond to a variety of intracellular and extracellular signals. These responses often necessitate the... (Review)
Review
Plants have developed fine-tuned cellular mechanisms to respond to a variety of intracellular and extracellular signals. These responses often necessitate the rearrangement of the plant cytoskeleton to modulate cell shape and/or to guide vesicle trafficking. At the cell periphery, both actin filaments and microtubules associate with the plasma membrane that acts as an integrator of the intrinsic and extrinsic environments. At this membrane, acidic phospholipids such as phosphatidic acid, and phosphoinositides contribute to the selection of peripheral proteins and thereby regulate the organization and dynamic of the actin and microtubules. After recognition of the importance of phosphatidic acid on cytoskeleton dynamics and rearrangement, it became apparent that the other lipids might play a specific role in shaping the cytoskeleton. This review focuses on the emerging role of the phosphatidylinositol 4,5-bisphosphate for the regulation of the peripherical cytoskeleton during cellular processes such as cytokinesis, polar growth, biotic and abiotic responses.
Topics: Phosphatidylinositols; Cytoskeleton; Microtubules; Actins; Cell Membrane; Actin Cytoskeleton; Plants
PubMed: 37084498
DOI: 10.1016/j.pbi.2023.102365 -
Molecular Biology of the Cell May 2022Specific lipid species play central roles in cell biology. Their presence or enrichment in individual membranes can control properties or direct protein localization...
Specific lipid species play central roles in cell biology. Their presence or enrichment in individual membranes can control properties or direct protein localization and/or activity. Therefore, probes to detect and observe these lipids in intact cells are essential tools in the cell biologist's freezer box. Herein, we discuss genetically encoded lipid biosensors, which can be expressed as fluorescent protein fusions to track lipids in living cells. We provide a state-of-the-art list of the most widely available and reliable biosensors and highlight new probes (circa 2018-2021). Notably, we focus on advances in biosensors for phosphatidylinositol, phosphatidic acid, and PI 3-kinase lipid products.
Topics: Biosensing Techniques; Fluorescent Dyes; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Transport
PubMed: 35420888
DOI: 10.1091/mbc.E21-07-0363 -
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