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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 Research Oct 2021Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid...
Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).
Topics: Biological Phenomena; Cell Line, Tumor; Cell Proliferation; Hippo Signaling Pathway; Humans; Phosphatidic Acids; Phosphoproteins; Protein Serine-Threonine Kinases; RNA, Long Noncoding; Signal Transduction; YAP-Signaling Proteins
PubMed: 34267352
DOI: 10.1038/s41422-021-00530-9 -
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 -
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 -
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 -
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 -
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 -
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 -
Nature Communications Oct 2023Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted...
Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.
Topics: Animals; Male; Mice; Adipocytes, Brown; Adipose Tissue, Brown; Lipocalin-2; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Plasmalogens; Thermogenesis
PubMed: 37872178
DOI: 10.1038/s41467-023-42473-2