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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 -
Drug Target Insights 2020Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which... (Review)
Review
INTRODUCTION
Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes.
METHODS
Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance.
RESULTS
The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption.
CONCLUSION
Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.
PubMed: 33510571
DOI: 10.33393/dti.2020.2185 -
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 -
Traffic (Copenhagen, Denmark) Jan 2020Many plasma membrane (PM) functions depend on the cholesterol concentration in the PM in strikingly nonlinear, cooperative ways: fully functional in the presence of... (Review)
Review
Many plasma membrane (PM) functions depend on the cholesterol concentration in the PM in strikingly nonlinear, cooperative ways: fully functional in the presence of physiological cholesterol levels (35~45 mol%), and nonfunctional below 25 mol% cholesterol; namely, still in the presence of high concentrations of cholesterol. This suggests the involvement of cholesterol-based complexes/domains formed cooperatively. In this review, by examining the results obtained by using fluorescent lipid analogs and avoiding the trap of circular logic, often found in the raft literature, we point out the fundamental similarities of liquid-ordered (Lo)-phase domains in giant unilamellar vesicles, Lo-phase-like domains formed at lower temperatures in giant PM vesicles, and detergent-resistant membranes: these domains are formed by cooperative interactions of cholesterol, saturated acyl chains, and unsaturated acyl chains, in the presence of >25 mol% cholesterol. The literature contains evidence, indicating that the domains formed by the same basic cooperative molecular interactions exist and play essential roles in signal transduction in the PM. Therefore, as a working definition, we propose that raft domains in the PM are liquid-like molecular complexes/domains formed by cooperative interactions of cholesterol with saturated acyl chains as well as unsaturated acyl chains, due to saturated acyl chains' weak multiple accommodating interactions with cholesterol and cholesterol's low miscibility with unsaturated acyl chains and TM proteins. Molecules move within raft domains and exchange with those in the bulk PM. We provide a logically established collection of fluorescent lipid probes that preferentially partition into raft and non-raft domains, as defined here, in the PM.
Topics: Cell Membrane; Cholesterol; Lipids; Membrane Microdomains; Unilamellar Liposomes
PubMed: 31760668
DOI: 10.1111/tra.12718 -
BioEssays : News and Reviews in... Feb 2016The fundamental mechanisms of protein and lipid organization at the plasma membrane have continued to engage researchers for decades. Among proposed models, one idea has... (Review)
Review
The fundamental mechanisms of protein and lipid organization at the plasma membrane have continued to engage researchers for decades. Among proposed models, one idea has been particularly successful which assumes that sterol-dependent nanoscopic phases of different lipid chain order compartmentalize proteins, thereby modulating protein functionality. This model of membrane rafts has sustainably sparked the fields of membrane biophysics and biology, and shifted membrane lipids into the spotlight of research; by now, rafts have become an integral part of our terminology to describe a variety of cell biological processes. But is the evidence clear enough to continue supporting a theoretical concept which has resisted direct proof by observation for nearly twenty years? In this essay, we revisit findings that gave rise to and substantiated the raft hypothesis, discuss its impact on recent studies, and present alternative mechanisms to account for plasma membrane heterogeneity.
Topics: Cell Membrane; Membrane Lipids; Membrane Proteins
PubMed: 26666984
DOI: 10.1002/bies.201500150 -
Membranes Oct 2020Nano-domains are sub-light-diffraction-sized heterogeneous areas in the plasma membrane of cells, which are involved in cell signalling and membrane trafficking.... (Review)
Review
Nano-domains are sub-light-diffraction-sized heterogeneous areas in the plasma membrane of cells, which are involved in cell signalling and membrane trafficking. Throughout the last thirty years, these nano-domains have been researched extensively and have been the subject of multiple theories and models: the lipid raft theory, the fence model, and the protein oligomerization theory. Strong evidence exists for all of these, and consequently they were combined into a hierarchal model. Measurements of protein and lipid diffusion coefficients and patterns have been instrumental in plasma membrane research and by extension in nano-domain research. This has led to the development of multiple methodologies that can measure diffusion and confinement parameters including single particle tracking, fluorescence correlation spectroscopy, image correlation spectroscopy and fluorescence recovery after photobleaching. Here we review the performance and strengths of these methods in the context of their use in identification and characterization of plasma membrane nano-domains.
PubMed: 33138102
DOI: 10.3390/membranes10110314 -
Autophagy Sep 2021Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously...
Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes. ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; VDAC1/porin: voltage dependent anion channel 1.
Topics: Autophagosomes; Autophagy; Lipids; Mitochondria; Mitochondrial Membranes
PubMed: 33034545
DOI: 10.1080/15548627.2020.1834207 -
Frontiers in Cell and Developmental... 2020The structure and organization of cellular membranes have received intense interest, particularly in investigations of the raft hypothesis. The vast majority of these... (Review)
Review
The structure and organization of cellular membranes have received intense interest, particularly in investigations of the raft hypothesis. The vast majority of these investigations have focused on the plasma membrane of mammalian cells, yielding significant progress in understanding membrane heterogeneity in terms of lipid composition, molecular structure, dynamic regulation, and functional relevance. In contrast, investigations on lipid organization in other membrane systems have been comparatively scarce, despite the likely relevance of membrane domains in these contexts. In this review, we summarize recent observations on lipid organization in organellar membranes, including endoplasmic reticulum, Golgi, endo-lysosomes, lipid droplets, and secreted membranes like lung surfactant, milk fat globule membranes, and viral membranes. Across these non-plasma membrane systems, it seems that the biophysical principles underlying lipid self-organization contribute to lateral domains.
PubMed: 33330457
DOI: 10.3389/fcell.2020.580814 -
The Journal of Physical Chemistry. B Sep 2020Membrane proteins and lipids have the capacity to associate into lateral domains in cell membranes through mutual or collective interactions. Lipid rafts are functional...
Membrane proteins and lipids have the capacity to associate into lateral domains in cell membranes through mutual or collective interactions. Lipid rafts are functional lateral domains that are formed through collective interactions of certain lipids and which can include or exclude proteins. These domains have been implicated in cell signaling and protein trafficking and seem to be of importance for virus-host interactions. We therefore want to investigate if raft and viral membrane proteins present similar structural features, and how these features are distributed throughout viruses. For this purpose, we performed a bioinformatics analysis of raft and viral membrane proteins from available online databases and compared them to nonraft proteins. In general, transmembrane proteins of rafts and viruses had higher proportions of palmitoyl and phosphoryl residues compared to nonraft proteins. They differed in terms of transmembrane domain length and thickness, with viral proteins being generally shorter and having a smaller accessible surface area per residue. Nontransmembrane raft proteins had increased amounts of palmitoyl, prenyl, and phosphoryl moieties while their viral counterparts were largely myristoylated and phosphorylated. Several of these structural determinants such as phosphorylation are new to the raft field and are extensively discussed in terms of raft functionality and phase separation. Surprisingly, the proportion of palmitoylated viral transmembrane proteins was inversely correlated to the virus size which indicated the implication of palmitoylation in virus membrane curvature and possibly budding. The current results provide new insights into the raft-virus interplay and unveil possible targets for antiviral compounds.
Topics: Cell Membrane; Humans; Lipids; Lipoylation; Membrane Microdomains; Membrane Proteins; Viral Proteins
PubMed: 32813532
DOI: 10.1021/acs.jpcb.0c03435 -
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