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International Review of Cell and... 2016Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways... (Review)
Review
Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways that produce PE, highlights the importance of this essential phospholipid. The CDP-ethanolamine and phosphatidylserine decarboxylase pathways occur in different subcellular compartments and are the main sources of PE in cells. Mammalian development fails upon ablation of either pathway. Once made, PE has diverse cellular functions that include serving as a precursor for phosphatidylcholine and a substrate for important posttranslational modifications, influencing membrane topology, and promoting cell and organelle membrane fusion, oxidative phosphorylation, mitochondrial biogenesis, and autophagy. The importance of PE metabolism in mammalian health has recently emerged following its association with Alzheimer's disease, Parkinson's disease, nonalcoholic liver disease, and the virulence of certain pathogenic organisms.
Topics: Alzheimer Disease; Animals; Autophagy; Candida; Carboxy-Lyases; Cell Membrane; Cytidine Diphosphate; Ethanolamines; Humans; Lipid Metabolism; Methylation; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Parkinson Disease; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Prions; Protein Processing, Post-Translational; Virulence
PubMed: 26811286
DOI: 10.1016/bs.ircmb.2015.10.001 -
Biochimica Et Biophysica Acta.... Sep 2017Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most abundant phospholipids in all mammalian cell membranes. In the 1950s, Eugene Kennedy and... (Review)
Review
Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most abundant phospholipids in all mammalian cell membranes. In the 1950s, Eugene Kennedy and co-workers performed groundbreaking research that established the general outline of many of the pathways of phospholipid biosynthesis. In recent years, the importance of phospholipid metabolism in regulating lipid, lipoprotein and whole-body energy metabolism has been demonstrated in numerous dietary studies and knockout animal models. The purpose of this review is to highlight the unappreciated impact of phospholipid metabolism on health and disease. Abnormally high, and abnormally low, cellular PC/PE molar ratios in various tissues can influence energy metabolism and have been linked to disease progression. For example, inhibition of hepatic PC synthesis impairs very low density lipoprotein secretion and changes in hepatic phospholipid composition have been linked to fatty liver disease and impaired liver regeneration after surgery. The relative abundance of PC and PE regulates the size and dynamics of lipid droplets. In mitochondria, changes in the PC/PE molar ratio affect energy production. We highlight data showing that changes in the PC and/or PE content of various tissues are implicated in metabolic disorders such as atherosclerosis, insulin resistance and obesity. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.
Topics: Animals; Fatty Liver, Alcoholic; Humans; Intestinal Mucosa; Lipoproteins, VLDL; Liver; Liver Regeneration; Metabolic Diseases; Mitochondria; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Phosphatidylcholines; Phosphatidylethanolamines
PubMed: 28411170
DOI: 10.1016/j.bbamem.2017.04.006 -
Nature Aug 2022Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has...
Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.
Topics: Akkermansia; Cell Membrane; Cytokines; Homeostasis; Humans; Immunity; Inflammation Mediators; Phosphatidylethanolamines; Structure-Activity Relationship; Toll-Like Receptor 1; Toll-Like Receptor 2
PubMed: 35896748
DOI: 10.1038/s41586-022-04985-7 -
Molecular Cell Oct 2022The covalent conjugation of ubiquitin family proteins is a widespread post-translational protein modification. In the ubiquitin family, the ATG8 subfamily is exceptional...
The covalent conjugation of ubiquitin family proteins is a widespread post-translational protein modification. In the ubiquitin family, the ATG8 subfamily is exceptional because it is conjugated mainly to phospholipids. However, it remains unknown whether other ubiquitin family proteins are also conjugated to phospholipids. Here, we report that ubiquitin is conjugated to phospholipids, mainly phosphatidylethanolamine (PE), in yeast and mammalian cells. Ubiquitinated PE (Ub-PE) accumulates at endosomes and the vacuole (or lysosomes), and its level increases during starvation. Ub-PE is also found in baculoviruses. In yeast, PE ubiquitination is catalyzed by the canonical ubiquitin system enzymes Uba1 (E1), Ubc4/5 (E2), and Tul1 (E3) and is reversed by Doa4. Liposomes containing Ub-PE recruit the ESCRT components Vps27-Hse1 and Vps23 in vitro. Ubiquitin-like NEDD8 and ISG15 are also conjugated to phospholipids. These findings suggest that the conjugation to membrane phospholipids is not specific to ATG8 but is a general feature of the ubiquitin family.
Topics: Animals; Endosomal Sorting Complexes Required for Transport; Liposomes; Mammals; Phosphatidylethanolamines; Phospholipids; Receptors, Cytoplasmic and Nuclear; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination
PubMed: 36044902
DOI: 10.1016/j.molcel.2022.08.008 -
Traffic (Copenhagen, Denmark) Jan 2015Membranes of mammalian subcellular organelles contain defined amounts of specific phospholipids that are required for normal functioning of proteins in the membrane.... (Review)
Review
Membranes of mammalian subcellular organelles contain defined amounts of specific phospholipids that are required for normal functioning of proteins in the membrane. Despite the wide distribution of most phospholipid classes throughout organelle membranes, the site of synthesis of each phospholipid class is usually restricted to one organelle, commonly the endoplasmic reticulum (ER). Thus, phospholipids must be transported from their sites of synthesis to the membranes of other organelles. In this article, pathways and subcellular sites of phospholipid synthesis in mammalian cells are summarized. A single, unifying mechanism does not explain the inter-organelle transport of all phospholipids. Thus, mechanisms of phospholipid transport between organelles of mammalian cells via spontaneous membrane diffusion, via cytosolic phospholipid transfer proteins, via vesicles and via membrane contact sites are discussed. As an example of the latter mechanism, phosphatidylserine (PS) is synthesized on a region of the ER (mitochondria-associated membranes, MAM) and decarboxylated to phosphatidylethanolamine in mitochondria. Some evidence is presented suggesting that PS import into mitochondria occurs via membrane contact sites between MAM and mitochondria. Recent studies suggest that protein complexes can form tethers that link two types of organelles thereby promoting lipid transfer. However, many questions remain about mechanisms of inter-organelle phospholipid transport in mammalian cells.
Topics: Animals; Biological Transport; Endoplasmic Reticulum; Humans; Mitochondria; Mitochondrial Membranes; Phosphatidylethanolamines; Phospholipids
PubMed: 25243850
DOI: 10.1111/tra.12230 -
Nature Jul 2021T follicular helper (T) cells are crucial for B cell-mediated humoral immunity. Although transcription factors such as BCL6 drive the differentiation of T cells, it is...
T follicular helper (T) cells are crucial for B cell-mediated humoral immunity. Although transcription factors such as BCL6 drive the differentiation of T cells, it is unclear whether and how post-transcriptional and metabolic programs enforce T cell programming. Here we show that the cytidine diphosphate (CDP)-ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of T cells and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI-enzymes in the CDP-ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)-as selective post-transcriptional regulators of T cell differentiation that act by promoting the surface expression and functional effects of CXCR5. T cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP-ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP-choline pathway), in activated T cells impairs the differentiation of T cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for T cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.
Topics: Animals; B-Lymphocytes; CRISPR-Cas Systems; Cell Differentiation; Cytidine Diphosphate; Female; Gene Expression Regulation; Humans; Immunity, Humoral; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylethanolamines; Phosphotransferases (Alcohol Group Acceptor); RNA Nucleotidyltransferases; Receptors, CXCR5; Signal Transduction; T-Lymphocytes, Helper-Inducer
PubMed: 34234346
DOI: 10.1038/s41586-021-03692-z -
Molecular Cell May 2021Autophagy is a fundamental catabolic process that uses a unique post-translational modification, the conjugation of ATG8 protein to phosphatidylethanolamine (PE). ATG8...
Autophagy is a fundamental catabolic process that uses a unique post-translational modification, the conjugation of ATG8 protein to phosphatidylethanolamine (PE). ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway involving conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments, with key functions in immunity, vision, and neurobiology. It is widely assumed that CASM involves the same conjugation of ATG8 to PE, but this has not been formally tested. Here, we discover that all ATG8s can also undergo alternative lipidation to phosphatidylserine (PS) during CASM, induced pharmacologically, by LC3-associated phagocytosis or influenza A virus infection, in mammalian cells. Importantly, ATG8-PS and ATG8-PE adducts are differentially delipidated by the ATG4 family and bear different cellular dynamics, indicating significant molecular distinctions. These results provide important insights into autophagy signaling, revealing an alternative form of the hallmark ATG8 lipidation event. Furthermore, ATG8-PS provides a specific "molecular signature" for the non-canonical autophagy pathway.
Topics: Adaptor Proteins, Signal Transducing; Animals; Autophagosomes; Autophagy; Autophagy-Related Protein 8 Family; Autophagy-Related Proteins; Cysteine Endopeptidases; Female; HCT116 Cells; HEK293 Cells; HeLa Cells; Humans; Influenza A virus; Macrolides; Male; Mice; Microtubule-Associated Proteins; Monensin; Phagocytosis; Phosphatidylethanolamines; Phosphatidylserines; Protein Processing, Post-Translational; RAW 264.7 Cells; Signal Transduction
PubMed: 33909989
DOI: 10.1016/j.molcel.2021.03.020 -
Cell Metabolism Mar 2024Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under...
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
Topics: Animals; Mice; Diacylglycerol O-Acyltransferase; Endoplasmic Reticulum; Liver; Non-alcoholic Fatty Liver Disease; Phosphatidylethanolamines; Sterol Regulatory Element Binding Protein 1; Triglycerides
PubMed: 38340721
DOI: 10.1016/j.cmet.2024.01.011 -
Science Advances Feb 2023Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner...
Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
Topics: Mice; Animals; Uncoupling Protein 1; Phosphatidylethanolamines; Protons; Mitochondria; Thermogenesis; Obesity; Adenosine Triphosphate; Mice, Knockout
PubMed: 36827367
DOI: 10.1126/sciadv.ade7864 -
The Journal of Biological Chemistry Mar 2020An early exposure to lipid biochemistry in the laboratory of Konrad Bloch resulted in a fascination with the biosynthesis, structures, and functions of bacterial lipids....
An early exposure to lipid biochemistry in the laboratory of Konrad Bloch resulted in a fascination with the biosynthesis, structures, and functions of bacterial lipids. The discovery of plasmalogens (1-alk-1'-enyl, 2-acyl phospholipids) in anaerobic Gram-positive bacteria led to studies on the physical chemistry of these lipids and the cellular regulation of membrane lipid polymorphism in bacteria. Later studies in several laboratories showed that the formation of the alk-1-enyl ether bond involves an aerobic process in animal cells and thus is fundamentally different from that in anaerobic organisms. Our work provides evidence for an anaerobic process in which plasmalogens are formed from their corresponding diacyl lipids. Studies on the roles of phospholipases in revealed distinctions between its phospholipases and those previously discovered in other bacteria and showed how the enzymes are uniquely fitted to the intracellular lifestyle of this significant human pathogen.
Topics: Anaerobiosis; Bacteria, Anaerobic; Fatty Acids; Gram-Positive Bacteria; Lipids; Phosphatidylethanolamines; Plasmalogens
PubMed: 32221031
DOI: 10.1074/jbc.X120.013022