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Experimental Biology and Medicine... Oct 2019Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain... (Review)
Review
UNLABELLED
Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain types of proteins. Among these are various cell signaling proteins, which indicate that rafts play an important role in cell signal transduction pathways, including some involved in cancer development, progression, and invasiveness. Due to their increased cholesterol content, raft domains exhibit lower fluidity than the surrounding membrane. The cell membranes of some solid tumors, such as breast and prostate cancer, contain higher levels of cholesterol, which means larger raft domain can form in those membranes. This may stimulate signaling pathways to promote tumor growth and progression. This review focuses on the known raft-dependent regulatory mechanisms that promote prostate cancer progression.
IMPACT STATEMENT
Prostate cancer remains the most common malignancy and second most frequent cause of cancer-related death in men. Cholesterol levels are usually higher in prostate cancer cells. This affects the cell membrane composition, with cholesterol and sphingolipid-containing raft membrane domains becoming a greater component. In addition to polar lipids, these domains recruit and regulate certain types of protein, including various cell signaling proteins that are critical to cancer cell survival and invasiveness. This suggests that membrane rafts have a regulatory role in tumor progression, making them a potential target in prostate cancer treatment.
Topics: Animals; Caveolae; Cholesterol; Disease Progression; Humans; Male; Membrane Microdomains; Prostatic Neoplasms; Signal Transduction
PubMed: 31573840
DOI: 10.1177/1535370219870771 -
Cell Reports Oct 2023Fatty acids have long been considered essential to brain development; however, the involvement of their synthesis in nervous system formation is unclear. We generate...
Fatty acids have long been considered essential to brain development; however, the involvement of their synthesis in nervous system formation is unclear. We generate mice with knockout of GPSN2, an enzyme for synthesis of very-long-chain fatty acids (VLCFAs) and investigate the effects. Both GPSN2 and GPSN2 mice show abnormal neuronal networks as a result of impaired neuronal polarity determination. Lipidomics of GPSN2 embryos reveal that ceramide synthesis is specifically inhibited depending on FA length; namely, VLCFA-containing ceramide is reduced. We demonstrate that lipid rafts are highly enriched in growth cones and that GPSN2 neurons lose gangliosides in their membranes. Application of C24:0 ceramide, but not C16:0 ceramide or C24:0 phosphatidylcholine, to GPSN2 neurons rescues both neuronal polarity determination and lipid-raft density in the growth cone. Taken together, our results indicate that VLCFA synthesis contributes to physiological neuronal development in brain network formation, in particular neuronal polarity determination through the formation of lipid rafts.
Topics: Animals; Mice; Sphingolipids; Ceramides; Fatty Acids; Membrane Microdomains; Neurons
PubMed: 37816355
DOI: 10.1016/j.celrep.2023.113195 -
International Journal of Molecular... Oct 2020The mobility of cellular prion protein (PrP) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its... (Review)
Review
The mobility of cellular prion protein (PrP) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrP works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrP is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrP through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrP traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.
Topics: Animals; Cell Membrane; Humans; Membrane Microdomains; Models, Biological; Neurodegenerative Diseases; PrPC Proteins; Prion Diseases; Protein Transport; Signal Transduction
PubMed: 33092231
DOI: 10.3390/ijms21207763 -
Essays in Biochemistry Dec 2021Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are an unmet health need,... (Review)
Review
Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.
Topics: Alzheimer Disease; Homeostasis; Humans; Membrane Lipids; Membrane Microdomains
PubMed: 34623437
DOI: 10.1042/EBC20210026 -
Biophysical Journal Jun 2021The lipid-raft hypothesis postulates that cell membranes possess some degree of lateral organization. The hypothesis has attracted much attention while remaining...
The lipid-raft hypothesis postulates that cell membranes possess some degree of lateral organization. The hypothesis has attracted much attention while remaining controversial, with an underlying mechanism that remains elusive. One idea that supports rafts relies on the membrane lying near a critical point. Although supported by experimental evidence, holding a many-component membrane at criticality requires a delicate tuning of all components-a daunting task. Here, we propose a coherent framework to reconcile critical behavior and lipid regulation. Using a lattice model, we show that lipid regulation of a complex membrane, i.e., allowing composition to fluctuate based on relative chemical potentials, can lead to critical behavior. The results are robust against specific values of the chemical potentials. Instead of a conventional transition point, criticality is observed over a large temperature range. This surprising behavior arises from finite-size effects, causing nonequivalent time and space averages. The instantaneous lipid distribution effectively develops a translational symmetry, which we relate to long-wavelength Goldstone modes. The framework is robust and reproduces important experimental trends; membrane-demixing temperature closely follows cell-growth temperature. It also ensures criticality of fixed-composition extracts, such as giant plasma membrane vesicles. Our clear picture provides a strong argument in favor of the critical-membrane hypothesis, without the need for specific sensing mechanisms.
Topics: Cell Membrane; Lipids; Membrane Microdomains; Membranes; Temperature
PubMed: 33961864
DOI: 10.1016/j.bpj.2021.03.043 -
Frontiers in Immunology 2021Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global... (Review)
Review
Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.
Topics: COVID-19; Cholesterol; Humans; Hydroxychloroquine; Membrane Microdomains; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; beta-Cyclodextrins
PubMed: 34975904
DOI: 10.3389/fimmu.2021.796855 -
Microbiology and Molecular Biology... Nov 2020There is growing appreciation that the plasma membrane orchestrates a diverse array of functions by segregating different activities into specialized domains that vary... (Review)
Review
There is growing appreciation that the plasma membrane orchestrates a diverse array of functions by segregating different activities into specialized domains that vary in size, stability, and composition. Studies with the budding yeast have identified a novel type of plasma membrane domain known as the MCC (membrane compartment of Can1)/eisosomes that correspond to stable furrows in the plasma membrane. MCC/eisosomes maintain proteins at the cell surface, such as nutrient transporters like the Can1 arginine symporter, by protecting them from endocytosis and degradation. Recent studies from several fungal species are now revealing new functional roles for MCC/eisosomes that enable cells to respond to a wide range of stressors, including changes in membrane tension, nutrition, cell wall integrity, oxidation, and copper toxicity. The different MCC/eisosome functions are often intertwined through the roles of these domains in lipid homeostasis, which is important for proper plasma membrane architecture and cell signaling. Therefore, this review will emphasize the emerging models that explain how MCC/eisosomes act as hubs to coordinate cellular responses to stress. The importance of MCC/eisosomes is underscored by their roles in virulence for fungal pathogens of plants, animals, and humans, which also highlights the potential of these domains to act as novel therapeutic targets.
Topics: Amino Acid Transport Systems, Basic; Cell Membrane; Endocytosis; Fungi; Membrane Microdomains; Membrane Proteins; Morphogenesis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Stress, Physiological; Virulence
PubMed: 32938742
DOI: 10.1128/MMBR.00063-19 -
Plant Physiology Apr 2021REMORINs (REMs) are a plant-specific protein family, proposed regulators of membrane-associated molecular assemblies and well-established markers of plasma membrane... (Review)
Review
REMORINs (REMs) are a plant-specific protein family, proposed regulators of membrane-associated molecular assemblies and well-established markers of plasma membrane nanodomains. REMs play a diverse set of functions in plant interactions with pathogens and symbionts, responses to abiotic stresses, hormone signaling and cell-to-cell communication. In this review, we highlight the established and more putative roles of REMs throughout the literature. We discuss the physiological functions of REMs, the mechanisms underlying their nanodomain-organization and their putative role as regulators of nanodomain-associated molecular assemblies. Furthermore, we discuss how REM phosphorylation may regulate their functional versatility. Overall, through data-mining and comparative analysis of the literature, we suggest how to further study the molecular mechanisms underpinning the functions of REMs.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Membrane; Membrane Microdomains; Plant Proteins
PubMed: 33793872
DOI: 10.1093/plphys/kiaa063 -
Frontiers in Immunology 2022T cells are master regulators of the immune response tuning, among others, B cells, macrophages and NK cells. To exert their functions requiring high sensibility and... (Review)
Review
T cells are master regulators of the immune response tuning, among others, B cells, macrophages and NK cells. To exert their functions requiring high sensibility and specificity, T cells need to integrate different stimuli from the surrounding microenvironment. A finely tuned signalling compartmentalization orchestrated in dynamic platforms is an essential requirement for the proper and efficient response of these cells to distinct triggers. During years, several studies have depicted the pivotal role of the cytoskeleton and lipid microdomains in controlling signalling compartmentalization during T cell activation and functions. Here, we discuss mechanisms responsible for signalling amplification and compartmentalization in T cell activation, focusing on the role of CD28, chemokine receptors and the actin cytoskeleton. We also take into account the detrimental effect of mutations carried by distinct signalling proteins giving rise to syndromes characterized by defects in T cell functionality.
Topics: CD28 Antigens; Immunological Synapses; Membrane Microdomains; Receptors, Chemokine; Signal Transduction
PubMed: 35983040
DOI: 10.3389/fimmu.2022.938004 -
International Journal of Molecular... Mar 2020Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and... (Review)
Review
Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane-cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by palmitoylation and myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes.
Topics: Animals; Endocytosis; Humans; Lipoylation; Membrane Microdomains; Membrane Proteins; Phosphatidylinositol 4,5-Diphosphate; Signal Transduction
PubMed: 32225034
DOI: 10.3390/ijms21072283