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Trends in Cell Biology May 2020The lipid raft hypothesis postulates that lipid-lipid interactions can laterally organize biological membranes into domains of distinct structures, compositions, and... (Review)
Review
The lipid raft hypothesis postulates that lipid-lipid interactions can laterally organize biological membranes into domains of distinct structures, compositions, and functions. This proposal has in equal measure exhilarated and frustrated membrane research for decades. While the physicochemical principles underlying lipid-driven domains has been explored and is well understood, the existence and relevance of such domains in cells remains elusive, despite decades of research. Here, we review the conceptual underpinnings of the raft hypothesis and critically discuss the supporting and contradicting evidence in cells, focusing on why controversies about the composition, properties, and even the very existence of lipid rafts remain unresolved. Finally, we highlight several recent breakthroughs that may resolve existing controversies and suggest general approaches for moving beyond questions of the existence of rafts and towards understanding their physiological significance.
Topics: Animals; Humans; Membrane Lipids; Membrane Microdomains; Models, Biological; Nanoparticles
PubMed: 32302547
DOI: 10.1016/j.tcb.2020.01.009 -
Molecular Cancer Apr 2017Cancer cells frequently display fundamentally altered cellular metabolism, which provides the biochemical foundation and directly contributes to tumorigenicity and... (Review)
Review
Cancer cells frequently display fundamentally altered cellular metabolism, which provides the biochemical foundation and directly contributes to tumorigenicity and malignancy. Rewiring of metabolic programmes, such as aerobic glycolysis and increased glutamine metabolism, are crucial for cancer cells to shed from a primary tumor, overcome the nutrient and energy deficit, and eventually survive and form metastases. However, the role of lipid metabolism that confers the aggressive properties of malignant cancers remains obscure. The present review is focused on key enzymes in lipid metabolism associated with metastatic disease pathogenesis. We also address the function of an important membrane structure-lipid raft in mediating tumor aggressive progression. We enumerate and integrate these recent findings into our current understanding of lipid metabolic reprogramming in cancer metastasis accompanied by new and exciting therapeutic implications.
Topics: Animals; Disease Progression; Humans; Hypoxia; Lipid Metabolism; Membrane Microdomains; Neoplasm Metastasis; Neoplasms
PubMed: 28399876
DOI: 10.1186/s12943-017-0646-3 -
Nature Reviews. Molecular Cell Biology Jun 2017Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A... (Review)
Review
Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large number of studies have focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed (or ordered) membrane domains that selectively recruit certain lipids and proteins. Recent studies have yielded new insights into this mechanism and its relevance in vivo, owing primarily to the development of improved biochemical and biophysical technologies.
Topics: Animals; Cell Membrane; Humans; Membrane Lipids; Membrane Microdomains
PubMed: 28356571
DOI: 10.1038/nrm.2017.16 -
International Journal of Molecular... Oct 2019Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on... (Review)
Review
Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on the activation of cells from both the innate and the adaptive immune system, although the mechanisms for such regulation are diverse. First, as a constitutive part of the cellular membrane, omega-3 fatty acids can regulate cellular membrane properties, such as membrane fluidity or complex assembly in lipid rafts. In recent years, however, a new role for omega-3 fatty acids and their derivatives as signaling molecules has emerged. In this review, we describe the latest findings describing the effects of omega-3 fatty acids on different cells from the immune system and their possible molecular mechanisms.
Topics: Adaptive Immunity; Animals; Cell Membrane; Fatty Acids, Omega-3; Humans; Immunity, Innate; Membrane Fluidity; Membrane Microdomains
PubMed: 31614433
DOI: 10.3390/ijms20205028 -
Current Biology : CB Apr 2018The plasma membrane is a ∼4 nm thick phospholipid bilayer that defines the boundary of a cell, segregating internal content from the external environment. Its... (Review)
Review
The plasma membrane is a ∼4 nm thick phospholipid bilayer that defines the boundary of a cell, segregating internal content from the external environment. Its hydrophobic interior presents a barrier to the exchange of ions and polar solutes between the inside and outside of the cell, as well as to the spontaneous reorientation of lipids between the two leaflets of the bilayer. Specific transport systems, e.g. ion channels and lipid flippases, are needed to enable the passage of these molecules across the plasma membrane at physiologically relevant rates. Although the influential fluid mosaic membrane model of 1972 depicted the membrane as an archipelago of protein islands within a uniform sea of lipids, its micrometer-scale lateral heterogeneity was recognized relatively quickly, evolving into the current picture of structural granularity at the nanoscale.
Topics: Biological Transport; Cell Membrane; Hydrodynamics; Lipid Bilayers; Lipid Metabolism; Lipids; Membrane Microdomains; Membrane Proteins
PubMed: 29689220
DOI: 10.1016/j.cub.2018.01.007 -
International Journal of Molecular... Sep 2021Glycosphingolipids (GSLs), together with cholesterol, sphingomyelin (SM), and glycosylphosphatidylinositol (GPI)-anchored and membrane-associated signal transduction... (Review)
Review
Glycosphingolipids (GSLs), together with cholesterol, sphingomyelin (SM), and glycosylphosphatidylinositol (GPI)-anchored and membrane-associated signal transduction molecules, form GSL-enriched microdomains. These specialized microdomains interact in a manner with various immune receptors, affecting immune receptor-mediated signaling. This, in turn, results in the regulation of a broad range of immunological functions, including phagocytosis, cytokine production, antigen presentation and apoptosis. In addition, GSLs alone can regulate immunological functions by acting as ligands for immune receptors, and exogenous GSLs can alter the organization of microdomains and microdomain-associated signaling. Many pathogens, including viruses, bacteria and fungi, enter host cells by binding to GSL-enriched microdomains. Intracellular pathogens survive inside phagocytes by manipulating intracellular microdomain-driven signaling and/or sphingolipid metabolism pathways. This review describes the mechanisms by which GSL-enriched microdomains regulate immune signaling.
Topics: Animals; Antigen Presentation; Apoptosis; Glycosphingolipids; Humans; Membrane Microdomains; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 34502474
DOI: 10.3390/ijms22179565 -
Cancer Metastasis Reviews Jun 2020Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in... (Review)
Review
Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in cholesterol- and sphingolipid-enriched domains. Flotillin heterotetramers can assemble into large oligomers to form molecular scaffolds that regulate the clustering of at the plasma membrane and activity of several receptors. Moreover, flotillins are upregulated in many invasive carcinomas and also in sarcoma, and this is associated with poor prognosis and metastasis formation. When upregulated, flotillins promote plasma membrane invagination and induce an endocytic pathway that allows the targeting of cargo proteins in the late endosomal compartment in which flotillins accumulate. These late endosomes are not degradative, and participate in the recycling and secretion of protein cargos. The cargos of this Upregulated Flotillin-Induced Trafficking (UFIT) pathway include molecules involved in signaling, adhesion, and extracellular matrix remodeling, thus favoring the acquisition of an invasive cellular behavior leading to metastasis formation. Thus, flotillin presence from the plasma membrane to the late endosomal compartment influences the activity, and even modifies the trafficking and fate of key protein cargos, favoring the development of diseases, for instance tumors. This review summarizes the current knowledge on flotillins and their role in cancer development focusing on their function in cellular membrane remodeling and vesicular trafficking regulation.
Topics: Animals; Carcinogenesis; Cell Membrane; Humans; Membrane Microdomains; Membrane Proteins; Neoplasms
PubMed: 32297092
DOI: 10.1007/s10555-020-09873-y -
Circulation Research Feb 2016Elevated levels of cholesteryl ester (CE)-enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of... (Review)
Review
Elevated levels of cholesteryl ester (CE)-enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of low-density lipoprotein cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can be either re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP-binding cassette transporter A1-mediated efflux. Because cholesterol is an essential component of all cellular membranes, some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ATP-binding cassette transporter A1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor apolipoprotein AI (apoAI) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified, CE droplets accumulate and microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor oversensitization. The availability of apoAI or other amphipathic α-helix-rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation.
Topics: ATP Binding Cassette Transporter 1; Animals; Arteries; Atherosclerosis; Cholesterol; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Esterification; Foam Cells; Humans; Hydrolysis; Inflammation; Lymphocyte Activation; Membrane Microdomains; T-Lymphocytes
PubMed: 26892966
DOI: 10.1161/CIRCRESAHA.115.306246 -
Bone Research Nov 2023The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the... (Review)
Review
The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the development of therapeutic strategies for these diseases. Strong experimental evidence supports the existence of membrane microdomains in osteoclasts (OCs). However, the potential membrane microdomains and the crucial mechanisms underlying their roles in OCs have not been fully characterized. Membrane microdomain components, such as scaffolding proteins and the actin cytoskeleton, as well as the roles of individual membrane proteins, need to be elucidated. In this review, we discuss the compositions and critical functions of membrane microdomains that determine the biological behavior of OCs through the three main stages of the OC life cycle.
Topics: Osteoclasts; Membrane Proteins; Membrane Microdomains; Cell Membrane Structures
PubMed: 37989999
DOI: 10.1038/s41413-023-00294-5 -
Current Opinion in Lipidology Oct 2017Reception and transmission of signals across the plasma membrane has been a function generally attributed to transmembrane proteins. In the last 3 years, however, a... (Review)
Review
PURPOSE OF REVIEW
Reception and transmission of signals across the plasma membrane has been a function generally attributed to transmembrane proteins. In the last 3 years, however, a growing number of reports have further acknowledged important contributions played by membrane lipids in the process of signal transduction.
RECENT FINDINGS
In particular, the constituency of membrane lipids can regulate how proteins with SH2 domains and molecules like K-Ras expose their catalytic domains to the cytosol and interact with effectors and second messengers. Recent reports have also shown that the degree of saturation of phospholipids can reduce the activation of certain G-protein-coupled receptors, and signaling downstream to Toll-like receptor 4 with consequences to nuclear factor kappa B activation and inflammation. Levels of specific gangliosides in the membrane were reported to activate integrins in a cell-autonomous manner affecting tumor cell migration. Furthermore, high resolution of the association of cholesterol with the smoothened receptor has clarified its participation in sonic hedgehog signaling. These are some of the key advancements that have further propelled our understanding of the broad versatile contributions of membrane lipids in signal transduction.
SUMMARY
As we gain definitive detail regarding the impact of lipid-protein interactions and their consequences to cell function, the options for therapeutic targeting expand with the possibility of greater specificity.
Topics: Animals; Humans; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Phospholipids; Signal Transduction
PubMed: 28692598
DOI: 10.1097/MOL.0000000000000443