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The EMBO Journal Apr 2023The maintenance of sodium/potassium (Na /K ) homeostasis in plant cells is essential for salt tolerance. Plants export excess Na out of cells mainly through the Salt...
The maintenance of sodium/potassium (Na /K ) homeostasis in plant cells is essential for salt tolerance. Plants export excess Na out of cells mainly through the Salt Overly Sensitive (SOS) pathway, activated by a calcium signal; however, it is unknown whether other signals regulate the SOS pathway and how K uptake is regulated under salt stress. Phosphatidic acid (PA) is emerging as a lipid signaling molecule that modulates cellular processes in development and the response to stimuli. Here, we show that PA binds to the residue Lys57 in SOS2, a core member of the SOS pathway, under salt stress, promoting the activity and plasma membrane localization of SOS2, which activates the Na /H antiporter SOS1 to promote the Na efflux. In addition, we reveal that PA promotes the phosphorylation of SOS3-like calcium-binding protein 8 (SCaBP8) by SOS2 under salt stress, which attenuates the SCaBP8-mediated inhibition of Arabidopsis K transporter 1 (AKT1), an inward-rectifying K channel. These findings suggest that PA regulates the SOS pathway and AKT1 activity under salt stress, promoting Na efflux and K influx to maintain Na /K homeostasis.
Topics: Arabidopsis; Arabidopsis Proteins; Homeostasis; Phosphatidic Acids; Potassium; Protein Serine-Threonine Kinases; Salt Stress; Sodium
PubMed: 36811145
DOI: 10.15252/embj.2022112401 -
Cell Jul 2018The inner nuclear membrane (INM) encases the genome and is fused with the outer nuclear membrane (ONM) to form the nuclear envelope. The ONM is contiguous with the...
The inner nuclear membrane (INM) encases the genome and is fused with the outer nuclear membrane (ONM) to form the nuclear envelope. The ONM is contiguous with the endoplasmic reticulum (ER), the main site of phospholipid synthesis. In contrast to the ER and ONM, evidence for a metabolic activity of the INM has been lacking. Here, we show that the INM is an adaptable membrane territory capable of lipid metabolism. S. cerevisiae cells target enzymes to the INM that can promote lipid storage. Lipid storage involves the synthesis of nuclear lipid droplets from the INM and is characterized by lipid exchange through Seipin-dependent membrane bridges. We identify the genetic circuit for nuclear lipid droplet synthesis and a role of these organelles in regulating this circuit by sequestration of a transcription factor. Our findings suggest a link between INM metabolism and genome regulation and have potential relevance for human lipodystrophy.
Topics: Cell Nucleus; Diglycerides; Endoplasmic Reticulum; Lipid Droplets; Lipid Metabolism; Lipids; Membrane Lipids; Membrane Proteins; Nuclear Envelope; Phosphatidic Acids; Saccharomyces cerevisiae
PubMed: 29937227
DOI: 10.1016/j.cell.2018.05.047 -
Cell Feb 2024Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA...
Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA homeostasis is tightly regulated and intertwined with ROS signaling upon immune elicitation remains elusive. We report here that Arabidopsis diacylglycerol kinase 5 (DGK5) regulates plant pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). The pattern recognition receptor (PRR)-associated kinase BIK1 phosphorylates DGK5 at Ser-506, leading to a rapid PA burst and activation of plant immunity, whereas PRR-activated intracellular MPK4 phosphorylates DGK5 at Thr-446, which subsequently suppresses DGK5 activity and PA production, resulting in attenuated plant immunity. PA binds and stabilizes the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD), regulating ROS production in plant PTI and ETI, and their potentiation. Our data indicate that distinct phosphorylation of DGK5 by PRR-activated BIK1 and MPK4 balances the homeostasis of cellular PA burst that regulates ROS generation in coordinating two branches of plant immunity.
Topics: Arabidopsis; Arabidopsis Proteins; Diacylglycerol Kinase; NADPH Oxidases; Phosphatidic Acids; Phosphorylation; Plant Immunity; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Receptors, Pattern Recognition
PubMed: 38244548
DOI: 10.1016/j.cell.2023.12.030 -
Advances in Biological Regulation Jan 2017Lipids play a vital role in the health and functioning of neurons and interest in the physiological role of neuronal lipids is certainly increasing. One neuronal... (Review)
Review
Lipids play a vital role in the health and functioning of neurons and interest in the physiological role of neuronal lipids is certainly increasing. One neuronal function in which neuronal lipids appears to play key roles in neurotransmission. Our understanding of the role of lipids in the synaptic vesicle cycle and neurotransmitter release is becoming increasingly more important. Much of the initial research in this area has highlighted the major roles played by the phosphoinositides (PtdIns), diacylglycerol (DAG), and phosphatidic acid (PtdOH). Of these, PtdOH has not received as much attention as the other lipids although its role and metabolism appears to be extremely important. This lipid has been shown to play a role in modulating both exocytosis and endocytosis although its precise role in either process is not well defined. The currently evidence suggest this lipid likely participates in key processes by altering membrane architecture necessary for membrane fusion, mediating the penetration of membrane proteins, serving as a precursor for other important SV cycling lipids, or activating essential enzymes. In this review, we address the sources of PtdOH, the enzymes involved in its production, the regulation of these enzymes, and its potential roles in neurotransmission in the central nervous system.
Topics: Animals; Biological Transport; Cell Membrane; Central Nervous System; Diglycerides; Endocytosis; Exocytosis; Humans; Lipid Metabolism; Neurons; Phosphatidic Acids; Phosphatidylinositol 4,5-Diphosphate; Synaptic Transmission; Synaptic Vesicles
PubMed: 27671966
DOI: 10.1016/j.jbior.2016.09.004 -
Advances in Biological Regulation Jan 2022Mammalian diacylglycerol kinases (DGKs) are a group of enzymes that catalyze the ATP-dependent phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid... (Review)
Review
Mammalian diacylglycerol kinases (DGKs) are a group of enzymes that catalyze the ATP-dependent phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PtdOH). In doing so, they modulate the levels of these two important signaling lipids. Currently, ten mammalian DGKs are organized into five classes that vary with respect to domain organization, regulation, and cellular/subcellular distribution. As lipids play critical roles in cells, it is not surprising that there is increasing interest in understanding the mechanism underlying the catalysis and regulation of lipid modulating enzymes such as DGKs. However, there are no solved 3D structures for any of the eukaryotic DGKs. In this review, we summarize what is known and the current challenges in determining the structures of these important enzymes. In addition to gain critical insights into their mechanisms of catalysis and regulation, DGK structures will provide a platform for the design of isoform specific inhibitors.
Topics: Animals; Diacylglycerol Kinase; Humans; Mammals; Phosphatidic Acids; Phosphorylation; Protein Isoforms; Signal Transduction
PubMed: 34922895
DOI: 10.1016/j.jbior.2021.100847 -
FEBS Letters Sep 2019Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a... (Review)
Review
Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from -1 to -2 and this change stabilizes protein-lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.
Topics: Animals; Cell Membrane; Humans; Membrane Fusion; Phosphatidic Acids
PubMed: 31365767
DOI: 10.1002/1873-3468.13563 -
Trends in Endocrinology and Metabolism:... Mar 2023mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1... (Review)
Review
mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1 in response to nutrients and growth factors. We review structural findings and propose a model for PA activation of mTORC1. PA binds to a highly conserved sequence in the α4 helix of the FK506 binding protein 12 (FKBP12)/rapamycin-binding (FRB) domain of mTOR. It is proposed that PA binding to two adjacent positively charged amino acids breaks and shortens the C-terminal region of helix α4. This has profound consequences for both substrate binding and the catalytic activity of mTORC1.
Topics: Humans; Phosphatidic Acids; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Amino Acids
PubMed: 36732094
DOI: 10.1016/j.tem.2023.01.004 -
Handbook of Experimental Pharmacology 2020Phospholipases D (PLDs) catalyze hydrolysis of the diester bond of phospholipids to generate phosphatidic acid and the free lipid headgroup. In mammals, PLD enzymes... (Review)
Review
Phospholipases D (PLDs) catalyze hydrolysis of the diester bond of phospholipids to generate phosphatidic acid and the free lipid headgroup. In mammals, PLD enzymes comprise the intracellular enzymes PLD1 and PLD2 and possibly the proteins encoded by related genes, as well as a class of cell surface and secreted enzymes with structural homology to ectonucleotide phosphatases/phosphodiesterases as typified by autotaxin (ENPP2) that have lysoPLD activities. Genetic and pharmacological loss-of-function approaches implicate these enzymes in intra- and intercellular signaling mediated by the lipid products phosphatidic acid, lysophosphatidic acid, and their metabolites, while the possibility that the water-soluble product of their reactions is biologically relevant has received far less attention. PLD1 and PLD2 are highly selective for phosphatidylcholine (PC), whereas autotaxin has broader substrate specificity for lysophospholipids but by virtue of the high abundance of lysophosphatidylcholine (LPC) in extracellular fluids predominantly hydrolyses this substrate. In all cases, the water-soluble product of these PLD activities is choline. Although choline can be formed de novo by methylation of phosphatidylethanolamine, this activity is absent in most tissues, so mammals are effectively auxotrophic for choline. Dietary consumption of choline in both free and esterified forms is substantial. Choline is necessary for synthesis of the neurotransmitter acetylcholine and of the choline-containing phospholipids PC and sphingomyelin (SM) and also plays a recently appreciated important role as a methyl donor in the pathways of "one-carbon (1C)" metabolism. This review discusses emerging evidence that some of the biological functions of these intra- and extracellular PLD enzymes involve generation of choline with a particular focus on the possibility that these choline and PLD dependent processes are dysregulated in cancer.
Topics: Animals; Choline; Humans; Hydrolysis; Neoplasms; Phosphatidic Acids; Phospholipase D; Signal Transduction
PubMed: 32086667
DOI: 10.1007/164_2019_320 -
Progress in Lipid Research Jan 2021Phospholipase D (PLD) and its metabolic active product phosphatidic acid (PA) engage in a wide range of physiopathologic processes in the cell. PLDs have been considered... (Review)
Review
Phospholipase D (PLD) and its metabolic active product phosphatidic acid (PA) engage in a wide range of physiopathologic processes in the cell. PLDs have been considered as a potential and promising drug target. Recently, the crystal structures of PLDs in mammalian and plant have been solved at atomic resolution. These achievements allow us to understand the structural differences among different species of PLDs and the functions of their key domains. In this review, we summarize the sequence and structure of different species of PLD isoforms, and discuss the structural mechanisms for PLD interactions with their binding partners and the functions of each key domain in the regulation of PLDs activation and catalytic reaction.
Topics: Animals; Phosphatidic Acids; Phospholipase D; Plants; Protein Isoforms
PubMed: 33181180
DOI: 10.1016/j.plipres.2020.101070 -
Trends in Cell Biology Jan 2018Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids.... (Review)
Review
Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases. Moreover, lipid-modifying enzymes such as phospholipases and lipid phosphatases may organize local lipid composition to spatially and temporarily coordinate a balance between fusion and division to establish mitochondrial morphology.
Topics: Cardiolipins; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Phosphatidic Acids
PubMed: 28911913
DOI: 10.1016/j.tcb.2017.08.011