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Frontiers in Bioscience (Landmark... Jan 2015The structural properties of the lipids forming biological membranes determine a very high level of lateral organization within membranes. Lipid-driven membrane... (Review)
Review
The structural properties of the lipids forming biological membranes determine a very high level of lateral organization within membranes. Lipid-driven membrane organization allows the segregation of membrane-associated components into membrane lipid domains, now worldwide known as lipid rafts, acting as dynamic platforms for signal transduction, protein processing and membrane turnover. Many processes necessary to the correct functions of nervous system occur in lipid rafts and are dependent on lipid raft organization. Thus, an altered lipid composition frequently occurring in neurodegenerative diseases leads to anomalous lipid raft organization and then to deregulated cell signaling.
Topics: Animals; Carbohydrate Sequence; Gangliosides; Humans; Membrane Microdomains; Molecular Sequence Data; Nervous System; Signal Transduction
PubMed: 25553451
DOI: 10.2741/4309 -
International Journal of Molecular... Dec 2020Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes,... (Review)
Review
Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis, ganglioside synthases, and their degradation, glycosidases. The dysregulation of their abundance results in rare and common diseases. In this review, we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.
Topics: Animals; Cell Membrane; Gangliosides; Glomerular Filtration Barrier; Humans; Podocytes
PubMed: 33348903
DOI: 10.3390/ijms21249645 -
Cell Communication and Signaling : CCS Apr 2015Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly... (Review)
Review
Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals evidence that dynasore reduces labile cholesterol in the plasma membrane, and disrupts lipid raft organization, in a dynamin-independent manner. To explore the role of dynamin it is important to use multiple dynamin inhibitors, alongside the use of dynamin mutants and RNA interference targeting genes encoding dynamin. On the other hand, dynasore provides an interesting tool to explore the regulation of cholesterol in plasma membranes.
Topics: Animals; Cell Membrane; Cholesterol; Dynamins; Enzyme Inhibitors; Humans; Hydrazones
PubMed: 25889964
DOI: 10.1186/s12964-015-0102-1 -
FEBS Open Bio Sep 2023Gangliosides are functional components of membrane lipid rafts that control critical functions in cell communication. Many pathologies involve raft gangliosides, which... (Review)
Review
Gangliosides are functional components of membrane lipid rafts that control critical functions in cell communication. Many pathologies involve raft gangliosides, which therefore represent an approach of choice for developing innovative therapeutic strategies. Beginning with a discussion of what a disease is (and is not), this review lists the major human pathologies that involve gangliosides, which includes cancer, diabetes, and infectious and neurodegenerative diseases. In most cases, the problem is due to a protein whose binding to gangliosides either creates a pathological condition or impairs a physiological function. Then, I draw up an inventory of the different molecular mechanisms of protein-ganglioside interactions. I propose to classify the ganglioside-binding domains of proteins into four categories, which I name GBD-1, GBD-2, GBD-3, and GBD-4. This structural and functional classification could help to rationalize the design of innovative molecules capable of disrupting the binding of selected proteins to gangliosides without generating undesirable effects. The biochemical specificities of gangliosides expressed in the human brain must also be taken into account to improve the reliability of animal models (or any animal-free alternative) of Alzheimer's and Parkinson's diseases.
Topics: Humans; Gangliosides; Reproducibility of Results; Parkinson Disease; Brain; Membrane Microdomains
PubMed: 37052878
DOI: 10.1002/2211-5463.13612 -
Chemistry and Physics of Lipids Nov 2018About twenty years ago, the functional lipid raft model of the plasma membrane was published. It took into account decades of research showing that cellular membranes... (Review)
Review
About twenty years ago, the functional lipid raft model of the plasma membrane was published. It took into account decades of research showing that cellular membranes are not just homogenous mixtures of lipids and proteins. Lateral anisotropy leads to assembly of membrane domains with specific lipid and protein composition regulating vesicular traffic, cell polarity, and cell signaling pathways in a plethora of biological processes. However, what appeared to be a clearly defined entity of clustered raft lipids and proteins became increasingly fluid over the years, and many of the fundamental questions about biogenesis and structure of lipid rafts remained unanswered. Experimental obstacles in visualizing lipids and their interactions hampered progress in understanding just how big rafts are, where and when they are formed, and with which proteins raft lipids interact. In recent years, we have begun to answer some of these questions and sphingolipids may take center stage in re-defining the meaning and functional significance of lipid rafts. In addition to the archetypical cholesterol-sphingomyelin raft with liquid ordered (Lo) phase and the liquid-disordered (Ld) non-raft regions of cellular membranes, a third type of microdomains termed ceramide-rich platforms (CRPs) with gel-like structure has been identified. CRPs are "ceramide rafts" that may offer some fresh view on the membrane mesostructure and answer several critical questions for our understanding of lipid rafts.
Topics: Animals; Humans; Membrane Microdomains; Sphingolipids
PubMed: 30194926
DOI: 10.1016/j.chemphyslip.2018.08.003 -
FEBS Letters Jun 2015Upon fusion of multivesicular bodies (MVBs) with the plasma membrane, intraluminal vesicles (ILVs) are released into the extracellular space as exosomes. Since the lipid... (Review)
Review
Upon fusion of multivesicular bodies (MVBs) with the plasma membrane, intraluminal vesicles (ILVs) are released into the extracellular space as exosomes. Since the lipid composition of the exosomal membrane resembles that of raft microdomains, the inward budding process involves the raft-like region of the MVB limiting membrane. Although published research suggests that cellular RNAs may be selectively sorted into exosomes, the molecular mechanisms remain elusive. In this review, we suggest that there is a continuous interaction of cellular RNAs with the outer (cytoplasmic) surface of MVBs and that the selection for incorporation of these RNAs into ILVs is based on their affinity to the raft-like region in the outer layer of the MVB membrane.
Topics: Animals; Cell Membrane; Exosomes; Humans; Membrane Lipids; Membrane Microdomains; Models, Biological; Multivesicular Bodies; RNA; RNA-Binding Proteins
PubMed: 25937124
DOI: 10.1016/j.febslet.2015.04.036 -
Cellular & Molecular Biology Letters Oct 2023Membrane rafts play a crucial role in the regulation of many important biological processes. Our previous data suggest that specific interactions of flotillins with MPP1...
BACKGROUND
Membrane rafts play a crucial role in the regulation of many important biological processes. Our previous data suggest that specific interactions of flotillins with MPP1 are responsible for membrane raft domain organization and regulation in erythroid cells. Interaction of the flotillin-based protein network with specific membrane components underlies the mechanism of raft domain formation and regulation, including in cells with low expression of MPP1.
METHODS
We sought to identify other flotillin partners via the immobilized recombinant flotillin-2-based affinity approach and mass spectrometry technique. The results were further confirmed via immunoblotting and via co-immunoprecipitation. In order to study the effect of the candidate protein on the physicochemical properties of the plasma membrane, the gene was knocked down via siRNA, and fluorescence lifetime imaging microscopy and spot-variation fluorescence correlation spectroscopy was employed.
RESULTS
EFR3A was identified as a candidate protein that interacts with flotillin-2. Moreover, this newly discovered interaction was demonstrated via overlay assay using recombinant EFR3A and flotillin-2. EFR3A is a stable component of the detergent-resistant membrane fraction of HeLa cells, and its presence was sensitive to the removal of cholesterol. While silencing the EFR3A gene, we observed decreased order of the plasma membrane of living cells or giant plasma membrane vesicles derived from knocked down cells and altered mobility of the raft probe, as indicated via fluorescence lifetime imaging microscopy and spot-variation fluorescence correlation spectroscopy. Moreover, silencing of EFR3A expression was found to disturb epidermal growth factor receptor and phospholipase C gamma phosphorylation and affect epidermal growth factor-dependent cytosolic Ca concentration.
CONCLUSIONS
Altogether, our results suggest hitherto unreported flotillin-2-EFR3A interaction, which might be responsible for membrane raft organization and regulation. This implies participation of this interaction in the regulation of multiple cellular processes, including those connected with cell signaling which points to the possible role in human health, in particular human cancer biology.
Topics: Humans; Cell Membrane; Epidermal Growth Factor; HeLa Cells; Protein Binding; Membrane Microdomains; Adaptor Proteins, Signal Transducing; Membrane Proteins
PubMed: 37880612
DOI: 10.1186/s11658-023-00497-y -
Aging Nov 2023Recently we have shown that adipokine visfatin-induced NLRP3 inflammasome activation contributes to podocyte injury. However, the molecular mechanisms of how...
Recently we have shown that adipokine visfatin-induced NLRP3 inflammasome activation contributes to podocyte injury. However, the molecular mechanisms of how visfatin-induces the Nlrp3 inflammasome activation and podocyte damage is still unknown. The present study tested whether membrane raft (MR) redox signalling pathway plays a central role in visfatin-induced NLRP3 inflammasomes formation and activation in podocytes. Upon visfatin stimulation an aggregation of NADPH oxidase subunits, gp91phox and p47phox was observed in the membrane raft (MR) clusters, forming a MR redox signalling platform in podocytes. The formation of this signalling platform was blocked by prior treatment with MR disruptor MCD or NADPH oxidase inhibitor DPI. In addition, visfatin stimulation significantly increased the colocalization of Nlrp3 with Asc or Nlrp3 with caspase-1, IL-β production, cell permeability in podocytes compared to control cells. Pretreatment with MCD, DPI, WEHD significantly abolished the visfatin-induced colocalization of NLRP3 with Asc or NLRP3 with caspase-1, IL-1β production and cell permeability in podocytes. Furthermore, Immunofluorescence analysis demonstrated that visfatin treatment significantly decreased the podocin and nephrin expression (podocyte damage) and prior treatments with DPI, WEHD, MCD attenuated this visfatin-induced podocin and nephrin reduction. In conclusion, our results suggest that visfatin stimulates membrane raft clustering in the membrane of podocytes to form redox signaling platforms by aggregation and activation of NADPH oxidase subunits enhancing O production and leading to NLRP3 inflammasome activation in podocytes and ultimate podocyte injury.
Topics: Inflammasomes; Podocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Nicotinamide Phosphoribosyltransferase; NADPH Oxidases; Caspase 1; Oxidation-Reduction
PubMed: 38032896
DOI: 10.18632/aging.205243 -
Journal of the American Chemical Society Jan 2024The peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form of cell death. Peroxidation changes...
The peroxidation of membrane lipids by free radicals contributes to aging, numerous diseases, and ferroptosis, an iron-dependent form of cell death. Peroxidation changes the structure and physicochemical properties of lipids, leading to bilayer thinning, altered fluidity, and increased permeability of membranes in model systems. Whether and how lipid peroxidation impacts the lateral organization of proteins and lipids in biological membranes, however, remains poorly understood. Here, we employ cell-derived giant plasma membrane vesicles (GPMVs) as a model to investigate the impact of lipid peroxidation on ordered membrane domains, often termed membrane rafts. We show that lipid peroxidation induced by the Fenton reaction dramatically enhances the phase separation propensity of GPMVs into coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains and increases the relative abundance of the disordered phase. Peroxidation also leads to preferential accumulation of peroxidized lipids and 4-hydroxynonenal (4-HNE) adducts in the disordered phase, decreased lipid packing in both Lo and Ld domains, and translocation of multiple classes of raft proteins out of ordered domains. These findings indicate that the peroxidation of plasma membrane lipids disturbs many aspects of membrane rafts, including their stability, abundance, packing, and protein and lipid composition. We propose that these disruptions contribute to the pathological consequences of lipid peroxidation during aging and disease and thus serve as potential targets for therapeutic intervention.
Topics: Lipid Peroxidation; Phase Separation; Cell Membrane; Membrane Lipids; Proteins; Membrane Microdomains; Lipid Bilayers
PubMed: 38171000
DOI: 10.1021/jacs.3c10132 -
Molecules (Basel, Switzerland) Oct 2020Membrane palmitoylated proteins (MPPs) are a subfamily of a larger group of multidomain proteins, namely, membrane-associated guanylate kinases (MAGUKs). The ubiquitous... (Review)
Review
Membrane palmitoylated proteins (MPPs) are a subfamily of a larger group of multidomain proteins, namely, membrane-associated guanylate kinases (MAGUKs). The ubiquitous expression and multidomain structure of MPPs provide the ability to form diverse protein complexes at the cell membranes, which are involved in a wide range of cellular processes, including establishing the proper cell structure, polarity and cell adhesion. The formation of MPP-dependent complexes in various cell types seems to be based on similar principles, but involves members of different protein groups, such as 4.1-ezrin-radixin-moesin (FERM) domain-containing proteins, polarity proteins or other MAGUKs, showing their multifaceted nature. In this review, we discuss the function of the MPP family in the formation of multiple protein complexes. Notably, we depict their significant role for cell physiology, as the loss of interactions between proteins involved in the complex has a variety of negative consequences. Moreover, based on recent studies concerning the mechanism of membrane raft formation, we shed new light on a possible role played by MPPs in lateral membrane organization.
Topics: Animals; Cell Membrane; Humans; Lipoylation; Membrane Proteins
PubMed: 33114686
DOI: 10.3390/molecules25214954