Showing papers on "Membrane lipids published in 2014"
TL;DR: It is demonstrated that resistance to unfolding correlates with specific lipid-binding events, enabling a distinction to be made between lipids that merely bind from those that modulate membrane protein structure and/or function.
Abstract: Previous studies have established that the folding, structure and function of membrane proteins are influenced by their lipid environments and that lipids can bind to specific sites, for example, in potassium channels. Fundamental questions remain however regarding the extent of membrane protein selectivity towards lipids. Here we report a mass spectrometry approach designed to determine the selectivity of lipid binding to membrane protein complexes. We investigate the mechanosensitive channel of large conductance (MscL) from Mycobacterium tuberculosis and aquaporin Z (AqpZ) and the ammonia channel (AmtB) from Escherichia coli, using ion mobility mass spectrometry (IM-MS), which reports gas-phase collision cross-sections. We demonstrate that folded conformations of membrane protein complexes can exist in the gas phase. By resolving lipid-bound states, we then rank bound lipids on the basis of their ability to resist gas phase unfolding and thereby stabilize membrane protein structure. Lipids bind non-selectively and with high avidity to MscL, all imparting comparable stability; however, the highest-ranking lipid is phosphatidylinositol phosphate, in line with its proposed functional role in mechanosensation. AqpZ is also stabilized by many lipids, with cardiolipin imparting the most significant resistance to unfolding. Subsequently, through functional assays we show that cardiolipin modulates AqpZ function. Similar experiments identify AmtB as being highly selective for phosphatidylglycerol, prompting us to obtain an X-ray structure in this lipid membrane-like environment. The 2.3 A resolution structure, when compared with others obtained without lipid bound, reveals distinct conformational changes that re-position AmtB residues to interact with the lipid bilayer. Our results demonstrate that resistance to unfolding correlates with specific lipid-binding events, enabling a distinction to be made between lipids that merely bind from those that modulate membrane protein structure and/or function. We anticipate that these findings will be important not only for defining the selectivity of membrane proteins towards lipids, but also for understanding the role of lipids in modulating protein function or drug binding.
628 citations
TL;DR: It is shown that cells specifically regulate the localization of lipids to midbodies, membrane-based structures where cleavage occurs, and that cells actively regulate and modulate their lipid composition and localization during division.
257 citations
TL;DR: The yeast Saccharomyces cerevisiae has become a reliable model organism to study biochemistry, molecular biology, and cell biology of lipids and the link between lipid metabolic and dynamic processes is discussed.
Abstract: During the last decades, lipids have gained much attention due to their involvement in health and disease. Lipids are required for the formation of membranes and contribute to many different processes such as cell signaling, energy supply, and cell death. Various organelles such as the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets are involved in lipid metabolism. The yeast Saccharomyces cerevisiae has become a reliable model organism to study biochemistry, molecular biology, and cell biology of lipids. The availability of mutants bearing defects in lipid metabolic pathways and the ease of manipulation by culture conditions facilitated these investigations. Here, we summarize the current knowledge about lipid metabolism in yeast. We grouped this large topic into three sections dealing with (1) fatty acids; (2) membrane lipids; and (3) storage lipids. Fatty acids serve as building blocks for the synthesis of membrane lipids (phospholipids, sphingolipids) and storage lipids (triacylglycerols, steryl esters). Phospholipids, sterols, and sphingolipids are essential components of cellular membranes. Recent investigations addressing lipid synthesis, degradation, and storage as well as regulatory aspects are presented. The role of enzymes governing important steps of the different lipid metabolic pathways is described. Finally, the link between lipid metabolic and dynamic processes is discussed.
255 citations
TL;DR: Simulation of complex asymmetric plasma membrane model, which contains seven different lipids species including the glycolipid GM3 in the outer leaflet and the anionic lipid, phosphatidylinositol 4,5-bisphophate, in the inner leaflet, reveals emergent nanoscale membrane organization which may be coupled both to fluctuations in local membrane geometry and to interactions with proteins.
Abstract: Cell membranes are complex multicomponent systems, which are highly heterogeneous in the lipid distribution and composition. To date, most molecular simulations have focussed on relatively simple lipid compositions, helping to inform our understanding of in vitro experimental studies. Here we describe on simulations of complex asymmetric plasma membrane model, which contains seven different lipids species including the glycolipid GM3 in the outer leaflet and the anionic lipid, phosphatidylinositol 4,5-bisphophate (PIP2), in the inner leaflet. Plasma membrane models consisting of 1500 lipids and resembling the in vivo composition were constructed and simulations were run for 5 µs. In these simulations the most striking feature was the formation of nano-clusters of GM3 within the outer leaflet. In simulations of protein interactions within a plasma membrane model, GM3, PIP2, and cholesterol all formed favorable interactions with the model α-helical protein. A larger scale simulation of a model plasma membrane containing 6000 lipid molecules revealed correlations between curvature of the bilayer surface and clustering of lipid molecules. In particular, the concave (when viewed from the extracellular side) regions of the bilayer surface were locally enriched in GM3. In summary, these simulations explore the nanoscale dynamics of model bilayers which mimic the in vivo lipid composition of mammalian plasma membranes, revealing emergent nanoscale membrane organization which may be coupled both to fluctuations in local membrane geometry and to interactions with proteins.
202 citations
TL;DR: It is shown that there are indeed enough lipids to cover the cell surface entirely as a bilayer within the cell wall, validating the outer membrane model and suggesting the nature of the inner membrane might also contribute to generalized drug resistance.
Abstract: Mycobacterium species, including the human pathogen Mycobacterium tuberculosis, are unique among Gram-positive bacteria in producing a complex cell wall that contains unusual lipids and functions as a permeability barrier. Lipids in the cell wall were hypothesized to form a bilayer or outer membrane that would prevent the entry of chemotherapeutic agents, but this could not be tested because of the difficulty in extracting only the cell-wall lipids. We used reverse micellar extraction to achieve this goal and carried out a quantitative analysis of both the cell wall and the inner membrane lipids of Mycobacterium smegmatis. We found that the outer leaflet of the outer membrane contains a similar number of hydrocarbon chains as the inner leaflet composed of mycolic acids covalently linked to cell-wall arabinogalactan, thus validating the outer membrane model. Furthermore, we found that preliminary extraction with reverse micelles permitted the subsequent complete extraction of inner membrane lipids with chloroform–methanol–water, revealing that one-half of hydrocarbon chains in this membrane are contributed by an unusual lipid, diacyl phosphatidylinositol dimannoside. The inner leaflet of this membrane likely is composed nearly entirely of this lipid. Because it contains four fatty acyl chains within a single molecule, it may produce a bilayer environment of unusually low fluidity and may slow the influx of drugs, contributing to the general drug resistance phenotype of mycobacteria.
200 citations
TL;DR: The structure activity relationship of saponins regarding hemolysis and cancer cell death is examined and a critical analysis of these findings speculates on their potential to further develop new anticancer compounds.
Abstract: Saponins, amphiphiles of natural origin with numerous biological activities, are widely used in the cosmetic and pharmaceutical industry. Some saponins exhibit relatively selective cytotoxic effects on cancer cells but the tendency of saponins to induce hemolysis limits their anticancer potential. This review focused on the effects of saponin activity on membranes and consequent implications for red blood and cancer cells. This activity seems to be strongly related to the amphiphilic character of saponins that gives them the ability to self-aggregate and interact with membrane components such as cholesterol and phospholipids. Membrane interactions of saponins with artificial membrane models, red blood and cancer cells are reviewed with respect to their molecular structures. The review considered the mechanisms of these membrane interactions and their consequences including the modulation of membrane dynamics, interaction with membrane rafts, and membrane lysis. We summarized current knowledge concerning the mechanisms involved in the interactions of saponins with membrane lipids and examined the structure activity relationship of saponins regarding hemolysis and cancer cell death. A critical analysis of these findings speculates on their potential to further develop new anticancer compounds.
160 citations
TL;DR: Analysis of X-ray diffraction, electron crystallography and NMR data over 100 specific lipid binding sites on membrane proteins demonstrate tight lipid binding of both phospholipids and cholesterol to membrane proteins.
138 citations
TL;DR: The findings support the idea that a regulatory loop involving plasma membrane–associated phosphoinositides modulates apical–basal PIN polarity via crosstalk between auxin signaling and the PIN polarizing machinery and provide insight into the polar domain–delineating mechanisms in plant cells that depend on apical and basal distribution of membrane lipids and are essential for embryonic and postembryonic patterning.
Abstract: Cell polarity manifested by asymmetric distribution of cargoes, such as receptors and transporters, within the plasma membrane (PM) is crucial for essential functions in multicellular organisms. In plants, cell polarity (re)establishment is intimately linked to patterning processes. Despite the importance of cell polarity, its underlying mechanisms are still largely unknown, including the definition and distinctiveness of the polar domains within the PM. Here, we show in Arabidopsis thaliana that the signaling membrane components, the phosphoinositides phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] as well as PtdIns4P 5-kinases mediating their interconversion, are specifically enriched at apical and basal polar plasma membrane domains. The PtdIns4P 5-kinases PIP5K1 and PIP5K2 are redundantly required for polar localization of specifically apical and basal cargoes, such as PIN-FORMED transporters for the plant hormone auxin. As a consequence of the polarity defects, instructive auxin gradients as well as embryonic and postembryonic patterning are severely compromised. Furthermore, auxin itself regulates PIP5K transcription and PtdIns4P and PtdIns(4,5)P2 levels, in particular their association with polar PM domains. Our results provide insight into the polar domain–delineating mechanisms in plant cells that depend on apical and basal distribution of membrane lipids and are essential for embryonic and postembryonic patterning.
137 citations
TL;DR: The activation of T cells by skin oils suggested that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups, which points to a previously unknown mechanism of barrier immunity.
Abstract: T cells autoreactive to the antigen-presenting molecule CD1a are common in human blood and skin, but the search for natural autoantigens has been confounded by background T cell responses to CD1 proteins and self lipids. After capturing CD1a-lipid complexes, we gently eluted ligands while preserving non-ligand-bound CD1a for testing lipids from tissues. CD1a released hundreds of ligands of two types. Inhibitory ligands were ubiquitous membrane lipids with polar head groups, whereas stimulatory compounds were apolar oils. We identified squalene and wax esters, which naturally accumulate in epidermis and sebum, as autoantigens presented by CD1a. The activation of T cells by skin oils suggested that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups. Oily autoantigens naturally coat the surface of the skin; thus, this points to a previously unknown mechanism of barrier immunity.
132 citations
TL;DR: This review describes the current knowledge of the biosynthetic pathway of archaeal ether lipids; insights on the stability and robustness of Archaeal lipid membranes; and evolutionary aspects of the lipid divide and the LUCA and examines recent advances made in the field of pathway reconstruction in bacteria.
Abstract: A vital function of the cell membrane in all living organism is to maintain the membrane permeability barrier and fluidity. The composition of the phospholipid bilayer is distinct in archaea when compared to bacteria and eukarya. In archaea, isoprenoid hydrocarbon side chains are linked via an ether bond to the sn-glycerol-1-phosphate backbone. In bacteria and eukarya on the other hand, fatty acid side chains are linked via an ester bond to the sn-glycerol-3-phosphate backbone. The polar head groups are globally shared in the three domains of life. The unique membrane lipids of archaea have been implicated not only in the survival and adaptation of the organisms to extreme environments but also to form the basis of the membrane composition of the last universal common ancestor (LUCA). In nature, a diverse range of archaeal lipids is found, the most common are the diether (or archaeol) and the tetraether (or caldarchaeol) lipids that form a monolayer. Variations in chain length, cyclization and other modifications lead to diversification of these lipids. The biosynthesis of these lipids is not yet well understood however progress in the last decade has led to a comprehensive understanding of the biosynthesis of archaeol. This review describes the current knowledge of the biosynthetic pathway of archaeal ether lipids; insights on the stability and robustness of archaeal lipid membranes; and evolutionary aspects of the lipid divide and the last universal common ancestor LUCA. It examines recent advances made in the field of pathway reconstruction in bacteria.
130 citations
TL;DR: It is reported that varying the cohesive forces within nanofibres of supramolecular materials with nearly identical cationic and hydrophobic structure instruct cell death or cell survival.
Abstract: Many naturally occurring peptides containing cationic and hydrophobic domains have evolved to interact with mammalian cell membranes and have been incorporated into materials for non-viral gene delivery, cancer therapy, or treatment of microbial infections. Their electrostatic attraction to the negatively charged cell surface and hydrophobic interactions with the membrane lipids enable intracellular delivery or cell lysis. While the effects of hydrophobicity and cationic charge of soluble molecules on the cell membrane are well known, the interactions between materials with these molecular features and cells remain poorly understood. Here we report that varying the cohesive forces within nanofibres of supramolecular materials with nearly identical cationic and hydrophobic structure instruct cell death or cell survival. Weak intermolecular bonds promote cell death through disruption of lipid membranes, while materials reinforced by hydrogen bonds support cell viability. These findings provide new strategies to design biomaterials that interact with the cell membrane.
TL;DR: A brief historical perspective on the characterization of lipids in platelets is provided, then an overview of the new generation lipidomic approaches, their recent application to platelet biology, and future perspectives for research in this area are summarized.
Abstract: Lipids are diverse families of biomolecules that perform essential structural and signaling roles in platelets. Their formation and metabolism are tightly controlled by enzymes and signal transduction pathways, and their dysregulation leads to significant defects in platelet function and disease. Platelet activation is associated with significant changes to membrane lipids, and formation of diverse bioactive lipids plays essential roles in hemostasis. In recent years, new generation mass spectrometry analysis of lipids (termed lipidomics) has begun to alter our understanding of how these molecules participate in key cellular processes. Although the application of lipidomics to platelet biology is still in its infancy, seminal earlier studies have shaped our knowledge of how lipids regulate key aspects of platelet biology, including aggregation, shape change, coagulation, and degranulation, as well as how lipids generated by platelets influence other cells, such as leukocytes and the vascular wall, and thus how they regulate hemostasis, vascular integrity, and inflammation, as well as contribute to pathologies, including arterial/deep vein thrombosis and atherosclerosis. This review will provide a brief historical perspective on the characterization of lipids in platelets, then an overview of the new generation lipidomic approaches, their recent application to platelet biology, and future perspectives for research in this area. The major platelet-regulatory lipid families, their formation, metabolism, and their role in health and disease, will be summarized.
TL;DR: The results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing ofAmyloid precursor protein in AD subjects at initial neuropathologic stages.
30 Apr 2014
TL;DR: This chapter focuses on the aspects of lipid metabolism that differ from those of the better-studied gram-negative bacteria, and the primary focus is on Bacillus subtilis because of the availability of its genome sequence and its advantages in genetic analysis.
Abstract: This chapter focuses on the aspects of lipid metabolism that differ from those of the better-studied gram-negative bacteria. The primary focus is on Bacillus subtilis because of the availability of its genome sequence and its advantages in genetic analysis, but data from related species has been incorporated when appropriate. The chapter describes lipid biosynthetic pathways. Malonyl-coenzyme A (CoA) is utilized for fatty acid biosynthesis only after its conversion to malonyl-acyl carrier protein (ACP) by malonyl-CoA transacylase, the product of the fabD gene. Two general mechanisms have been described for the biosynthesis of long-chain, monounsaturated fatty acids in living cells. One of them (found only in bacteria) is independent of oxygen and consists of a branch point in the fatty acid synthesis pathway at the level of a C-10 intermediate. In this mechanism, a β-hydroxydecanoyl dehydrase converts (stereospecifically) the C-10 hydroxy intermediate to two isomers, the trans-2,3 and the cis-3,4 unsaturated C-10 intermediates, the first of which gives rise to normal saturated products while the second gives monounsaturated fatty acids. As the growth temperature is lowered, the proportion of low-melting-point fatty acids in the membrane lipids increases. The finding that the substrates for the ∆5-desaturase are membrane lipids provides the cell with a rapid mechanism for decreasing the fluidity of preexisting membranes upon temperature decrease. A focused attack using the information of the B. subtilis genome sequence should yield new clues to understanding membrane biogenesis and membrane differentiation in prokaryotes.
TL;DR: What has come to be known as melatonin's antioxidant cascade accounts, presumably in large part, for its ability to reduce oxidative damage, including that to PUFA, and the metabolites that are formed are also radical scavengers.
Abstract: Lipid peroxidation (LPO) occurs as a result of the oxidative deterioration of polyunsaturated fatty acids (PUFA), i.e., those that contain two or more carbon–carbon double bonds. The most apparent feature of the oxidative breakdown of lipids is rancidity, a problem that was recognized centuries ago during the storage of fats and oils. Rancidity persists as a widespread problem in today's society because of the common use of polyunsaturated fats and oils.
The outer limiting membrane of cells and membranes of subcellular organelles, e.g., mitochondria, liposomes, peroxisomes, etc., are generally rich in PUFA and their protection from oxidation is essential for the optimal function and survival of the cell. In addition to lipids, cell membranes also contain proteins in varying amounts depending on the unique physiology of the membrane. Thus, the inner mitochondrial membrane, because of its high density of respiratory complex proteins, contains only 20% lipids; this is also the case with chloroplast thylakoid membranes. In contrast, the myelin sheath surrounding axons are up to 80% lipid. Due to the differences in the percentage of lipids in membranes, they are subjected to different degrees of peroxidation.
Membranes are fluid structures and optimal membrane fluidity is required for their proper function. When membrane fatty acids are oxidized, cell membranes become viscous (more rigid). Many factors contribute to the oxidation of membrane lipids and, during aging, cell membranes become progressively more rancid and rigid; this contributes to the degenerative signs of aging.
The oxidation of lipids is a highly complex process that is initiated when a hydrogen atom is abstracted from a methylene (–CH2–) group by a free radical (Figure (Figure1).1). PUFA are particularly susceptible to peroxidative initiation because of their numerous carbon–carbon double bonds. Of the free radicals and other reactive oxygen (ROS) and reactive nitrogen species (RNS) generated within cells, the hydroxyl radical (•OH) is easily capable of initiating LPO. In contrast, the superoxide anion radical (O2•–) is not sufficiently reactive to abstract a hydrogen atom from a lipid molecule. As a consequence of the initiation of lipid breakdown, a lipid peroxyl radical (ROO•) is eventually generated. ROO• are highly reactive and are capable of abstracting a hydrogen atom from a neighboring lipid (causing another initiation event). This is referred to as the propagation phase of LPO. Due to this auto-oxidative chain reaction, a single initiation event could theoretically lead to the oxidation of all lipids in a cellular organelle, or in a cell. Other reactive species which initiate LPO include peroxynitrite anion (ONOO−) and singlet oxygen (1O2). Because of the highly destructive structural and functional nature of LPO, there is great interest in identifying molecules which reduce the initiation and/or progression of the denaturation of PUFA.
Figure 1
Schematic representations of lipid peroxidation and melatonin's antioxidant cascade. The metabolites of melatonin, i.e., c3OHM, AFMK, and AMK, are generated when the preceding molecule in the cascade functions in the detoxification of reactive oxygen ...
Melatonin and its derivatives as antioxidants
What has come to be known as melatonin's antioxidant cascade accounts, presumably in large part, for its ability to reduce oxidative damage, including that to PUFA (Tan et al., 2007). When melatonin functions in the detoxification of radicals, the metabolites that are formed are also radical scavengers. The initial derivative that is produced is cyclic 3-hydroxymelatonin (c3OHM) (Figure (Figure1).1). This derivative functions as a radical scavenger to generate N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) which, like its predecessor, neutralizes toxic ROS/RNS. In doing so AFMK is metabolized to N1-acetyl-5-methoxykynuramine (AMK). AMK likewise is capable of defeating radicals and beyond this there may yet be other derivatives that function as antioxidants.
Via this cascade of reactions, each molecule of melatonin is predicted to scavenge up to 10 ROS/RNS. This unique property of melatonin makes it highly effective in combatting oxidative stress and LPO. Melatonin is produced in many cells and its synthesis may be upregulated under conditions that elevate oxidative stress in mammals, as happens in plants (Arnao and Hernandez-Ruiz, 2013).
Besides its direct actions as a scavenger, melatonin also stimulates the activities of a variety of antioxidative enzymes including manganese and copper-zinc superoxide dismutase, glutathione peroxidase and reductase and glutamylcysteine ligase (Rodriguez et al., 2004). The combined actions as well as its function at the inner mitochondrial membrane where it limits electron leakage (called radical avoidance) makes melatonin exceptionally effective in reducing oxidative stress.
TL;DR: The focus of this review is the latest evidence regarding the impact of oleic acid and the minor constituents of virgin olive oil on the arrangement and behavior of lipid bilayers.
TL;DR: This article develops a viscous-elastic model for inhomogeneous membranes of the Helfrich type and finds that the lipids flow to accommodate changes in membrane curvature during protein adsorption, and shows that this change in membrane tension can have a functional impact such as altered response to pulling forces in the presence of proteins.
TL;DR: These various concepts of lipid synthesis, metabolism, and compartmentalization are reviewed and recent progress in understanding viral interactions with host cell lipids during entry and assembly is highlighted.
Abstract: For entry and infection viruses have developed numerous strategies to subjugate indispensable cellular factors and functions. Host cell lipids and cellular lipid synthesis machinery are no exception. Not only do viruses exploit existing lipid signalling and modifications for virus entry and trafficking, they also reprogram lipid synthesis, metabolism, and compartmentalization for assembly and egress. Here we review these various concepts and highlight recent progress in understanding viral interactions with host cell lipids during entry and assembly.
TL;DR: Studies in the rat show that, with respect to the general classes of fatty acids (saturated, monounsaturated and polyunsaturated) membrane fatty acid composition is homeostatically regulated despite diet variation, but this is not the case for fatty acids composition of storage lipids, which responds to diet variation.
Abstract: Fatty acids are essential for life because they are essential components of cellular membranes. Lower animals can synthesize all four classes of fatty acids from non-lipid sources, but both omega-6 and omega-3 cannot be synthesized de novo by ‘higher’ animals and are therefore essential components of their diet. The relationship between normal variation in diet fatty acid composition and membrane fatty acid composition is little investigated. Studies in the rat show that, with respect to the general classes of fatty acids (saturated, monounsaturated and polyunsaturated) membrane fatty acid composition is homeostatically regulated despite diet variation. This is not the case for fatty acid composition of storage lipids, which responds to diet variation. Polyunsaturated fatty acids are important determinants of physical and chemical properties of membranes. They are the substrates for lipid peroxidation and it is possible to calculate a peroxidation index (PI) for a particular membrane composition. Membrane PI appears to be homeostatically regulated with respect to diet PI. Membrane fatty acid composition varies among species and membrane PI is inversely correlated to longevity in mammals, birds, bivalve molluscs, honeybees and the nematode Caenorhabditis elegans.
TL;DR: The level of multiple lipid species were increased in infected cells, pointing to the induction of major alterations of cellular lipid metabolism by WNV infection, and the role of sphingolipids in the biogenesis of WNV was verified.
Abstract: West Nile virus (WNV) is an emerging zoonotic mosquito-borne flavivirus responsible for outbreaks of febrile illness and meningoencephalitis. The replication of WNV takes place on virus-modified membranes from the endoplasmic reticulum of the host cell, and virions acquire their envelope by budding into this organelle. Consistent with this view, the cellular biology of this pathogen is intimately linked to modifications of the intracellular membranes, and the requirement for specific lipids, such as cholesterol and fatty acids, has been documented. In this study, we evaluated the impact of WNV infection on two important components of cellular membranes, glycerophospholipids and sphingolipids, by mass spectrometry of infected cells. A significant increase in the content of several glycerophospholipids (phosphatidylcholine, plasmalogens, and lysophospholipids) and sphingolipids (ceramide, dihydroceramide, and sphingomyelin) was noticed in WNV-infected cells, suggesting that these lipids have functional roles during WNV infection. Furthermore, the analysis of the lipid envelope of WNV virions and recombinant virus-like particles revealed that their envelopes had a unique composition. The envelopes were enriched in sphingolipids (sphingomyelin) and showed reduced levels of phosphatidylcholine, similar to sphingolipid-enriched lipid microdomains. Inhibition of neutral sphingomyelinase (which catalyzes the hydrolysis of sphingomyelin into ceramide) by either pharmacological approaches or small interfering RNA-mediated silencing reduced the release of flavivirus virions as well as virus-like particles, suggesting a role of sphingomyelin-to-ceramide conversion in flavivirus budding and confirming the importance of sphingolipids in the biogenesis of WNV.
IMPORTANCE West Nile virus (WNV) is a neurotropic flavivirus spread by mosquitoes that can infect multiple vertebrate hosts, including humans. There is no specific vaccine or therapy against this pathogen licensed for human use. Since the multiplication of this virus is associated with rearrangements of host cell membranes, we analyzed the effect of WNV infection on different cellular lipids that constitute important membrane components. The levels of multiple lipid species were increased in infected cells, pointing to the induction of major alterations of cellular lipid metabolism by WNV infection. Interestingly, certain sphingolipids, which were increased in infected cells, were also enriched in the lipid envelope of the virus, thus suggesting a potential role during virus assembly. We further verified the role of sphingolipids in the production of WNV by means of functional analyses. This study provides new insight into the formation of flavivirus infectious particles and the involvement of sphingolipids in the WNV life cycle.
TL;DR: This article compares the amino acid sequences of the key enzymes of the archaeal ether-lipid biosynthesis pathway and critically evaluate past studies on the biochemical functions of these enzymes, and proposes an alternative archaealing lipid biosynthetic pathway that is based on a 'multiple-key, multiple-lock' mechanism.
Abstract: Archaea produce unique membrane lipids in which isoprenoid alkyl chains are bound to glycerol moieties via ether linkages As cultured representatives of the Archaea have become increasingly available throughout the past decade, archaeal genomic and membrane lipid-composition data have also become available In this Analysis article, we compare the amino acid sequences of the key enzymes of the archaeal ether-lipid biosynthesis pathway and critically evaluate past studies on the biochemical functions of these enzymes We propose an alternative archaeal lipid biosynthetic pathway that is based on a 'multiple-key, multiple-lock' mechanism
TL;DR: Evidence is presented that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes, and that autophagic-lysosomal dysfunction in T gCRND 8 brain impedes lysosomal turnover of lipids as well as proteins.
Abstract: Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer’s disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer’s disease.
TL;DR: It is established that arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, enhances touch sensation and mechanoelectrical transduction activity while incorporated into membrane phospholipids in C. elegans touch receptor neurons (TRNs), and proposed that this polyuns saturated fatty acid (PUFA) is needed for MeT channel activity.
TL;DR: These studies show that solid-state (13)C NMR spectroscopy is applicable to investigations of complex lipids and makes it possible to obtain structural parameters for biomembrane systems where isotope labeling may be prohibitive.
TL;DR: Recent clinical trials have shown the benefits of Lipid Replacement Therapy in restoring mitochondrial function and reducing fatigue in aged subjects and patients with a variety of clinical diagnoses that are characterized by loss of mitochondria function and include fatigue as a major symptom.
TL;DR: A simple method was devised to prepare large unilamellar model membrane vesicles that closely resemble mammalian plasma membranes in terms of their lipid composition and asymmetry and should be superior and more realistic model membranes for studies of lipid-lipid and lipid-protein interaction in a lipid environment that resembles that of mammalian plasma membrane.
Abstract: Lipid asymmetry, the difference in lipid distribution across the lipid bilayer, is one of the most important features of eukaryotic cellular membranes. However, commonly used model membrane vesicles cannot provide control of lipid distribution between inner and outer leaflets. We recently developed methods to prepare asymmetric model membrane vesicles, but facile incorporation of a highly controlled level of cholesterol was not possible. In this study, using hydroxypropyl-α-cyclodextrin based lipid exchange, a simple method was devised to prepare large unilamellar model membrane vesicles that closely resemble mammalian plasma membranes in terms of their lipid composition and asymmetry (sphingomyelin (SM) and/or phosphatidylcholine (PC) outside/phosphatidylethanolamine (PE) and phosphatidylserine (PS) inside), and in which cholesterol content can be readily varied between 0 and 50 mol%. We call these model membranes “artificial plasma membrane mimicking” (“PMm”) vesicles. Asymmetry was confirmed by both chemical labeling and measurement of the amount of externally-exposed anionic lipid. These vesicles should be superior and more realistic model membranes for studies of lipid-lipid and lipid-protein interaction in a lipid environment that resembles that of mammalian plasma membranes.
TL;DR: Analysis of patients with prosaposin deficiency revealed the accumulation of intra-endolysosmal vesicles and membrane structures (IM), suggesting inner membrane structures as platforms of sphingolipid degradation.
TL;DR: This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporter in cancer and in the tumor microenvironment.
Abstract: Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.
TL;DR: Reconstitution of vacuole fusion with all purified components reveals that high SNARE levels can mask the requirement for a complex mixture of vacUole lipids.
Abstract: Like other intracellular fusion events, the homotypic fusion of yeast vacuoles requires a Rab GTPase, a large Rab effector complex, SNARE proteins which can form a 4-helical bundle, and the SNARE disassembly chaperones Sec17p and Sec18p. In addition to these proteins, specific vacuole lipids are required for efficient fusion in vivo and with the purified organelle. Reconstitution of vacuole fusion with all purified components reveals that high SNARE levels can mask the requirement for a complex mixture of vacuole lipids. At lower, more physiological SNARE levels, neutral lipids with small headgroups that tend to form non-bilayer structures (phosphatidylethanolamine, diacylglycerol, and ergosterol) are essential. Membranes without these three lipids can dock and complete trans-SNARE pairing but cannot rearrange their lipids for fusion.
DOI: http://dx.doi.org/10.7554/eLife.01879.001
TL;DR: A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient.
Abstract: Lipids are unevenly distributed within and between cell membranes, thus defining organelle identity. Such distribution relies on local metabolic branches and mechanisms that move lipids. These processes are regulated by feedback mechanisms that decipher topographical information in organelle membranes and then regulate lipid levels or flows. In the endoplasmic reticulum, the major lipid source, transcriptional regulators and enzymes sense changes in membrane features to modulate lipid production. At the Golgi apparatus, lipid-synthesizing, lipid-flippase, and lipid-transport proteins (LTPs) collaborate to control lipid balance and distribution within the membrane to guarantee remodeling processes crucial for vesicular trafficking. Open questions exist regarding LTPs, which are thought to be lipid sensors that regulate lipid synthesis or carriers that transfer lipids between organelles across long distances or in contact sites. A novel model is that LTPs, by exchanging two different lipids, exploit one lipid gradient between two distinct membranes to build a second lipid gradient.