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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 -
Journal of Experimental & Clinical... Oct 2022Beta-1,3-galactosyltransferase-4 (B3GALT4) plays a critical regulatory role in tumor biology. However, the role of B3GALT4 in modulating the tumor microenvironment (TME)...
BACKGROUND
Beta-1,3-galactosyltransferase-4 (B3GALT4) plays a critical regulatory role in tumor biology. However, the role of B3GALT4 in modulating the tumor microenvironment (TME) of neuroblastoma (NB) remains unknown.
METHODS
Public datasets and clinical NB samples were collected to evaluate the expression and clinical significance of GD2 and B3GALT4 in NB patients. CCK-8, colony formation, and transwell assays and experiments in tumor-bearing mouse models were conducted to investigate the function of B3GALT4. Flow cytometry, ELISA, immunohistochemistry, immunofluorescence, western blotting, and chemotaxis assays were conducted to ascertain the immunomodulatory mechanism of B3GALT4. The combined therapeutic effect of the lipid raft inhibitor MβCD and anti-GD2 mAb was validated in a murine model of NB.
RESULTS
GD2 was overexpressed in NB tissues and high expression of GD2 was associated with poor prognosis in NB patients. B3GALT4 was downregulated in NB tissues, and low expression of B3GALT4 indicated poor prognosis in NB patients. Silencing B3GALT4 significantly enhanced tumor progression both in vitro and in vivo. Meanwhile, the overexpression of B3GALT4 increased the recruitment of CD8 T lymphocytes via the chemokines CXCL9 and CXCL10. Additionally, B3GALT4 regulated NB-cell GD2 expression and lipid raft formation. Mechanistically, B3GALT4 regulated the expression of CXCL9 and CXCL10 via the c-Met signaling in the lipid rafts and the downstream AKT/mTOR/IRF-1 pathway. The lipid raft inhibitor, MβCD, attenuated B3GALT4 deficiency-induced tumor progression and immune evasion. Last, MβCD combined with anti-GD2 mAb treatment significantly enhanced the antitumor effect and the infiltration of CD8 T cells.
CONCLUSIONS
Upregulation of B3GALT4 promotes the secretion of CXCL9 and CXCL10 to recruit CD8 T lymphocytes via the GD2-mediated lipid rafts and the c-Met/AKT/mTOR/IRF-1 pathway. Moreover, lipid raft inhibitors may enhance the efficacy of anti-GD2 immunotherapy for NB.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemokines; Galactosyltransferases; Gangliosides; Membrane Microdomains; Neuroblastoma; Proto-Oncogene Proteins c-akt; Sincalide; TOR Serine-Threonine Kinases; Tumor Microenvironment; Proto-Oncogene Proteins c-met
PubMed: 36284313
DOI: 10.1186/s13046-022-02523-x -
Open Biology Aug 2021Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of... (Review)
Review
Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood. Here, we review a newly discovered interaction between primary cilia and lipid raft dynamics that occurs during Akt signalling in adipogenesis. We also discuss the relationship between primary cilia and lipid raft-mediated Akt signalling in cancer biology. This review provides a novel perspective on primary cilia in the regulation of lipid raft dynamics.
Topics: Adipogenesis; Animals; Cilia; Humans; Membrane Microdomains; Signal Transduction
PubMed: 34428960
DOI: 10.1098/rsob.210130 -
Anatomical Record (Hoboken, N.J. : 2007) Jun 2020CD147 (basigin; EMMPRIN), hyaluronan, and hyaluronan receptors (e.g., CD44) are intimately involved in several phenomena that underlie malignancy. A major avenue whereby... (Review)
Review
CD147 (basigin; EMMPRIN), hyaluronan, and hyaluronan receptors (e.g., CD44) are intimately involved in several phenomena that underlie malignancy. A major avenue whereby they influence tumor progression is most likely their role in the characteristics of cancer stem cells (CSCs), subpopulations of tumor cells that exhibit chemoresistance, invasiveness, and potent tumorigenicity. Both CD147 and hyaluronan have been strongly implicated in chemoresistance and invasiveness, and may be drivers of CSC characteristics, since current evidence indicates that both are involved in epithelial-mesenchymal transition, a crucial process in the acquisition of CSC properties. Hyaluronan is a prominent constituent of the tumor microenvironment whose interactions with cell surface receptors influence several signaling pathways that lead to chemoresistance and invasiveness. CD147 is an integral plasma membrane glycoprotein of the Ig superfamily and cofactor in assembly and activity of monocarboxylate transporters (MCTs). CD147 stimulates hyaluronan synthesis and interaction of hyaluronan with its receptors, in particular CD44 and LYVE-1, which in turn result in activation of multiprotein complexes containing members of the membrane-type matrix metalloproteinase, receptor tyrosine kinase, ABC drug transporter, or MCT families within lipid raft domains. Multivalent hyaluronan-receptor interactions are essential for formation or stabilization of these lipid raft complexes and for downstream signaling pathways or transporter activities. We conclude that stimulation of hyaluronan-receptor interactions by CD147 and the consequent activities of these complexes may be critical to the properties of CSCs and their role in malignancy. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.
Topics: Basigin; Cell Membrane; Humans; Hyaluronan Receptors; Hyaluronic Acid; Membrane Microdomains; Neoplasms; Neoplastic Stem Cells
PubMed: 31090215
DOI: 10.1002/ar.24147 -
Journal of Lipid Research May 2020Lipid rafts regulate the initiation of cellular metabolic and signaling pathways by organizing the pathway components in ordered microdomains on the cell surface.... (Review)
Review
Lipid rafts regulate the initiation of cellular metabolic and signaling pathways by organizing the pathway components in ordered microdomains on the cell surface. Cellular responses regulated by lipid rafts range from physiological to pathological, and the success of a therapeutic approach targeting "pathological" lipid rafts depends on the ability of a remedial agent to recognize them and disrupt pathological lipid rafts without affecting normal raft-dependent cellular functions. In this article, concluding the Thematic Review Series on Biology of Lipid Rafts, we review current experimental therapies targeting pathological lipid rafts, including examples of inflammarafts and clusters of apoptotic signaling molecule-enriched rafts. The corrective approaches include regulation of cholesterol and sphingolipid metabolism and membrane trafficking by using HDL and its mimetics, LXR agonists, ABCA1 overexpression, and cyclodextrins, as well as a more targeted intervention with apoA-I binding protein. Among others, we highlight the design of antagonists that target inflammatory receptors only in their activated form of homo- or heterodimers, when receptor dimerization occurs in pathological lipid rafts. Other therapies aim to promote raft-dependent physiological functions, such as augmenting caveolae-dependent tissue repair. The overview of this highly dynamic field will provide readers with a view on the emerging concept of targeting lipid rafts as a therapeutic strategy.jlr;61/5/687/F1F1f1.
Topics: Animals; Humans; Membrane Microdomains; Molecular Targeted Therapy
PubMed: 32205411
DOI: 10.1194/jlr.TR120000658 -
Frontiers in Cellular and Infection... 2020Verotoxin, VT (aka Shiga toxin,Stx) is produced by enterohemorrhagic (EHEC) and is the key pathogenic factor in EHEC-induced hemolytic uremic syndrome (eHUS-hemolytic... (Review)
Review
Verotoxin, VT (aka Shiga toxin,Stx) is produced by enterohemorrhagic (EHEC) and is the key pathogenic factor in EHEC-induced hemolytic uremic syndrome (eHUS-hemolytic anemia/thrombocytopenia/glomerular infarct) which can follow gastrointestinal EHEC infection, particularly in children. This AB5 subunit toxin family bind target cell globotriaosyl ceramide (Gb), a glycosphingolipid (GSL) (aka CD77, pk blood group antigen) of the globoseries of neutral GSLs, initiating lipid raft-dependent plasma membrane Gb clustering, membrane curvature, invagination, scission, endosomal trafficking, and retrograde traffic via the TGN to the Golgi, and ER. In the ER, A/B subunits separate and the A subunit hijacks the ER reverse translocon (dislocon-used to eliminate misfolded proteins-ER associated degradation-ERAD) for cytosolic access. This property has been used to devise toxoid-based therapy to temporarily block ERAD and rescue the mutant phenotype of several genetic protein misfolding diseases. The A subunit avoids cytosolic proteosomal degradation, to block protein synthesis via its RNA glycanase activity. In humans, Gb is primarily expressed in the kidney, particularly in the glomerular endothelial cells. Here, Gb is in lipid rafts (more ordered membrane domains which accumulate GSLs/cholesterol) whereas renal tubular Gb is in the non-raft membrane fraction, explaining the basic pathology of eHUS (glomerular endothelial infarct). Females are more susceptible and this correlates with higher renal Gb expression. HUS can be associated with encephalopathy, more commonly following verotoxin 2 exposure. Gb is expressed in the microvasculature of the brain. All members of the VT family bind Gb, but with varying affinity. VT2e (pig edema toxin) binds Gb preferentially. Verotoxin-specific therapeutics based on chemical analogs of Gb, though effective , have failed . While some analogs are effective in animal models, there are no good rodent models of eHUS since Gb is not expressed in rodent glomeruli. However, the mouse mimics the neurological symptoms more closely and provides an excellent tool to assess therapeutics. In addition to direct cytotoxicity, other factors including VT-induced cytokine release and aberrant complement cascade, are now appreciated as important in eHUS. Based on atypical HUS therapy, treatment of eHUS patients with anticomplement antibodies has proven effective in some cases. A recent switch using stem cells to try to reverse, rather than prevent VT induced pathology may prove a more effective methodology.
Topics: Animals; Endothelial Cells; Escherichia coli; Hemolytic-Uremic Syndrome; Humans; Mice; Shiga Toxin; Shiga Toxin 1; Swine
PubMed: 32296648
DOI: 10.3389/fcimb.2020.00123 -
The Journal of Investigative Dermatology Feb 2022Single gene disorders are ideally suited to establish robust genotype‒phenotype correlations and provide excellent opportunities to understand molecular...
Single gene disorders are ideally suited to establish robust genotype‒phenotype correlations and provide excellent opportunities to understand molecular pathomechanisms with relevance to complex disorders. The observation that patients diagnosed with the same causative mutation can present with phenotypic disease variability illustrates the significant role of disease modifiers and warns against oversimplification. In a new article in the Journal of Investigative Dermatology, Zimmer et al. (2021) analyze two mutations located in the desmoglein (DSG) 1 transmembrane domain (TMD) and find that both mutants fail to assemble into desmosomes owing to reduced membrane trafficking and lipid raft targeting. One mutation maintained normal protein expression levels and turnover relative to those of wild-type (WT) DSG1, and behaved as a dominant negative. The second mutant showed reduced stability and increased turnover compared with WT DSG1 as well as reduced desmosome size and abundance. A full understanding of the TMD of DSG1 requires cell biological approaches, underscoring the value of cell biology in biomedical research in general.
Topics: Desmoglein 1; Desmosomes; Humans; Membrane Microdomains; Mutation
PubMed: 34799122
DOI: 10.1016/j.jid.2021.08.389 -
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 -
International Journal of Molecular... Aug 2020Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the... (Review)
Review
Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid rafts are spatially and compositionally heterogeneous in the single-cell membrane. In this review, we summarize our recent data on living platelets using two specific probes of raft components: lysenin as a probe of sphingomyelin-rich rafts and BCθ as a probe of cholesterol-rich rafts. Sphingomyelin-rich rafts that are spatially and functionally distinct from the cholesterol-rich rafts were found at spreading platelets. Fibrin is translocated to sphingomyelin-rich rafts and platelet sphingomyelin-rich rafts act as platforms where extracellular fibrin and intracellular actomyosin join to promote clot retraction. On the other hand, the collagen receptor glycoprotein VI is known to be translocated to cholesterol-rich rafts during platelet adhesion to collagen. Furthermore, the functional roles of platelet glycosphingolipids and platelet raft-binding proteins including G protein-coupled receptors, stomatin, prohibitin, flotillin, and HflK/C-domain protein family, tetraspanin family, and calcium channels are discussed.
Topics: Animals; Blood Platelets; Cell Membrane; Cholesterol; Fibrin; Glycosphingolipids; Humans; Membrane Microdomains; Signal Transduction; Sphingomyelins
PubMed: 32748854
DOI: 10.3390/ijms21155539