NPC1 binding to NBDcholesterol was competed by cholesterol, 25hydroxycholesterol, dihydroergosterol, and to a lesser but significant extent, the cationic sterol UA, but not epicholesterol This suggested that NPC1 distinguishes the orientation of the cholesterol hydroxyl group (consistent with Refs UA caused the accumulation of cholesterol in lysosomes where CSFV membrane fusion was speculated to impede • The data provides mechanistic insight into UA targeting NPC1 protein, which is responsible for cholesterol trafficking Abstract The level of cholesterol in host cells has been demonstrated to affect viral infectionNPC1 deficient mouse tissue and human fibroblasts treated with Ua show an increase of Beclin1 and LC3 levels1,4, suggesting that altered cholesterol distribution in NPC1 deficient cells promote autophagy as compensation for cholesterol accumulation within late
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U18666a npc1
U18666a npc1- UA binds NPC1 and block its function (Lu et al, 15) In this study, AY9944, Clomiphene, Ro 4071, and Itraconazole, which block NPC1 function similarly with UA ( Shoemaker et al, 13 , Trinh et al, 16 ), also exhibited type I FCoV replicationinhibitory effects, suggesting that type I FCoV replication was inhibited by UA is a cholesterol transport‐inhibiting agent that is used widely to mimic Niemann–Pick type C disease The effect of UA on tumour necrosis factor (TNF)‐α production in mouse macrophage cell line, RAW 264·7 cells and
Npc Intracellular Cholesterol Transporter 1 Npc1 Mediated Cholesterol Export From Lysosomes Journal Of Biological Chemistry
UA effectively inhibits NPC1 function and blocks cholesterol export from the LYs ( Liscum and Faust, 19;Lu et al, 15), and UAtreated cells survived amphotericin B UA is a cationic amphiphile that inhibit NPC1 function by directly binding to sterolsensing domain of NPC1 protein, phenocopying the effects of NPC1 mutation on intracellular cholesterol trafficking 29, 30The close connection between NPC1 and the drug UA, which causes NPC1like organelle defects, was established by rescuing drugtreated cells with overproduced NPC1 UA inhibits outward
title = "Identification of NPC1 as the target of UA, an inhibitor of lysosomal cholesterol export and Ebola infection", abstract = "NiemannPick C1 (NPC1) is a lysosomal membrane protein that exports cholesterol derived from receptormediated uptake of LDL, and it also mediates cellular entry of Ebola virusOur data showed that UA affected both the fusion and replication steps in the life cycle of the virus, but not its binding and entry steps The subsequent experiments confirmed that niemannpick C1 (NPC1), a lysosomal membrane protein that helps cholesterol to leave the lysosome, was affected by UA, which led to the accumulation of cholesterol in lysosomes and inhibition of Niemann–Pick C1 protein (NPC1) is a lateendosomal membrane protein required for transport of LDLderived cholesterol into cells and Ebola virus entry;
Figure 3 Distribution of NPC1 in UAtreated CHO/NPC1 cells On day 0, CHO/NPC1 cells were plated in medium A and incubated with 2 μg/ml UA On day 1, cells were incubated with 5 μ m LysoSensor Green DND153 for 2 h before fixation and stained for NPC1 (A) and filipin (B) Acidic organelles were visualized using the LysoSensor probe Ua, an amphipathic steroid, reproduces some features of NPC disease at the cellular level, at least in part by disrupting NPC1 function (21 – 24) A direct interaction between NPC1 and UA is proposed to be responsible for UAmediated lysosomal cholesterol accumulation ( 23 , 25 , 26 )Aconazole, or UA, but not with ketoconazole or compound A A similar pattern of competition was seen when UX was the crosslinker (Fig 3A, Right) These results indicate that PX and UX bind to NPC1, and that the binding site also recognizes itraconazole and UA, but not ketoconazole or compound A
Ebola Virus Entry Requires The Cholesterol Transporter Niemann Pick C1 Abstract Europe Pmc
Human Wt Fibroblasts Were Treated With Ua Or Quinacrine To Induce Download Scientific Diagram
Small molecules that induce a cellular phenotype similar to NPC1 deficiency, such as UA and imipramine, potently inhibited infection by rVSVGPEboV, even after a short exposure to the molecules Immunofluorescence microscopy demonstrated that wildtype cells treated with UA or cells lacking NPC1, VPS11, or VPS33A had an alteredNPC1 has not been found to be the cellular receptor for these viruses, so the adverse effects on viral replication after treatment with UA or NPC1 UA may act on the activity or synthesis of another protein or lipid which facilitates cholesterol movement , , , , thus accumulating cholesterol to massive levels in cells treated with this agent , , , and possibly altering the cellular distribution of NPC1 , , as observed in cells from NPC patients , ,
Effects Of Ua On Cellular Levels Of Free Cholesterolgm1 And Download Scientific Diagram
A Trimeric Rab7 Gef Controls Npc1 Dependent Lysosomal Cholesterol Export Nature Communications
WT Chinese hamster ovary (CHO) cells, NPC1 −/− CHO cells and WT CHO cells treated with UA (2 µg/ml for 72 h) were transfected with Sec61GFP for 24 h and incubated with Lysotracker Red (75 nM)Sidera et al 05), it is difficult to determine how much of its effects that are related to NPC1 inhibition We therefore tested Chinese Hamster Ovary wild type cells (CHOwt) and CHO NPC1null cells (CHO NPC1/) (all originally provided by The protein NPC1 controls intracellular cholesterol mobilization and deletion of NPC1 phenocopies the treatment of UA and causes cholesterol accumulation in LEs Reduction of NPC1 inhibits the activity of LBPA in membrane deformation 31 cells were treated with two different siRNAs targeting NPC1
Cholesterol Accumulation In Endosomes Of Cho Cells Does Not Inhibit Viral Fusion
Triazoles Inhibit Cholesterol Export From Lysosomes By Binding To Npc1 Pnas
The aim of this work was to assess whether the endosomal alterations that are observed in mouse and cellular models of NPC disease disrupt NGF signaling We used two different models NPC1deficient ( NPC1/) mice and PC12 cells treated with UA (PC12UA cells), a wellknown inducer of the NPC phenotype 28 – 31 UA, which is an inhibitor of intracellular cholesterol trafficking and has recently been shown to directly bind and inhibit NPC1 34, isMoreover, fibroblasts from NPC1 patients and UAtreated cells showed a lower percentage distribution of primary cilia and a significant reduction in median cilia length with respect to controls These are the first results demonstrating altered cytoplasmic expression of Ptc1 and reduced number and length of primary cilia, where Ptc1 is located, in fibroblasts from NPC1
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Npc Intracellular Cholesterol Transporter 1 Npc1 Mediated Cholesterol Export From Lysosomes Journal Of Biological Chemistry
U A has been used in fibroblast controls to study the mechanism of increase in autophagy in NiemannPick Disease Type C (NPC) cells Packaging 5, 25 mg in glass bottle Biochem/physiol Actions Inhibitor of cholesterol synthesis (inhibits desmosterol Δ24reductase) Weak inhibitor of hedgehog (hh) signaling Preparation NoteThe 3beta (2diethylaminoethoxy)androstenone hcl (ua), progesterone and several cationic amphiphilic drugs have been shown to alter the trafficking of a number of intracellular membrane proteins including cd63/lamp3, insulin growth factor 2/mannose 6phosphate receptor (igf2/mpr), and the niemannpick c1 gene product (npc1) as well as UA reproduces the inverse correlation between STARD and ACDase in Npc1/ PMH We next further characterized the relationship between STARD1 and ACDase Since ACDase is a lysosomal enzyme, we first addressed whether the decrease in ACDase expression in NPC cells could be a consequence of the accumulation of cholesterol in lysosomes
Npc1 Regulates Er Contacts With Endocytic Organelles To Mediate Cholesterol Egress Nature Communications
Dynamic Movements Of Organelles Containing Niemann Pick C1 Protein Npc1 Involvement In Late Endocytic Events Molecular Biology Of The Cell
Compound UA, extensively used as a pharmacological tool to study the role of NPC1, blocks intracellular cholesterol efflux mediated by NPC1 It has been demonstrated that UA can affect DENV entry and trafficking (Poh et al, 12) Ua, an amphipathic steroid, reproduces some features of NPC disease at the cellular level, at least in part by disrupting NPC1 function (21,–24) A direct interaction between NPC1 and UA is proposed to be responsible for UAmediated lysosomal cholesterol accumulation (23, 25, 26) BMP levels were quantified as described in SI Materials and Methods using fluorescence microscopy from images obtained with a x objective of cells stained with antiBMP antibody and AlexaFluor4conjugated secondary antibody in NPC1 (A), NPC2 (B) mutant, and 1 μM UAtreated normal cells Cells were incubated with 09 mM CD for ≈1
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Cholinergic Abnormalities Endosomal Alterations And Up Regulation Of Nerve Growth Factor Signaling In Niemann Pick Type C Disease Molecular Neurodegeneration Full Text
Figures and data in Identification of NPC1 as the target of UA, an inhibitor of lysosomal cholesterol export and Ebola infection eLife Biochemistry and Chemical Biology Cell Biology Identification of NPC1 as the target of UA, an inhibitor of lysosomal cholesterol export and Ebola infection Feiran Lu, Qiren Liang, Lina AbiMosleh,System (AcLDL UA or Npc1 null mutation) activated Tolllike receptor (TLR) signaling, leading to sustained phosphorylation of p38 mitogenactivated protein kinase and induction of p38 targets, including Ctsk, S100a8, Mmp8, and Mmp14 Studies in macrophages from knockout mice showed major roles for TLR4, following plasma membrane cholesterol Sterol trafficking beyond phagosomes and esterification was impaired by the NPC1 inhibitor UA NPC1 is a protein that mediates cholesterol export from late endosomes/lysosomes in mammalian cells
Npc1 Was Inhibited In 3t3 L1 Adipocytes Through Treatment With Ua Download Scientific Diagram
Cellular Mechanism Of Ua Mediated Apoptosis In Cultured Murine Cortical Neurons Bridging Niemann Pick Disease Type C And Alzheimer S Disease Sciencedirect
UA was used to induce NPC1 phenotype in unaffected cells of the control cell line Phorbol 12myristate 13acetate (PMA) was used to activate PKC Results Immunocytochemical detection of GFAP, vimentin and Ki67 revealed that NPC1 mutant glial cells undergo gliosisUA was used to induce NPC1 phenotyp e in unaffected cells of the control cell line Phorbol 12myristate 13acetate (PMA) was used to activate PKC Results Immunocytochemical detection of GF AP, vimentin and Ki67 revealed that NPC1 mutant glial cells undergo gliosisThe NPC1 protein also plays a crucial role in allowing Ebola viruses to infect animal cells and multiply UA is a drug that blocks the movement of cholesterol out of lysosomes and also inhibits Ebola virus infections, but it was not known what components it targets in cells
Niemann Pick Disease Type C1 Npc1 Lysosomal Lipid Storage Disease Download Scientific Diagram
Niemann Pick C1 Functions In Regulating Lysosomal Amine Content Sciencedirect
NPC1null cell model Since UA may influence APP processing enzymes directly Crestini et al 06( ;NPC1 binding to NBDcholesterol was competed by cholesterol, 25hydroxycholesterol, dihydroergosterol, and to a lesser but significant extent, the cationic sterol UA, but not epicholesterol This suggested that NPC1 distinguishes the orientation of the cholesterol hydroxyl group (consistent with RefsIdentification of NPC1 as the target of UA, an inhibitor of lysosomal cholesterol export and Ebola infection NiemannPick C1 (NPC1) is a lysosomal membrane protein that exports cholesterol derived from receptormediated uptake of LDL, and it also mediates cellular entry of Ebola virus
Inhibition Of Intracellular Cholesterol Transport Alters Presenilin Localization And Amyloid Precursor Protein Processing In Neuronal Cells Journal Of Neuroscience
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UA (designated U) is a derivative of androstenolone wherein the 3hydroxyl is modified as a diethylami noethyl ether, which will be charged (protonated) at neutral pH (pKa 941) As a control for Figure 1 Domain structure of human NiemannPick C1 (NPC1)Cells were briefly incubated with 10 mM methylamine hydrochloride and chased for cholesterol export for 1 h in 5% LPDS medium, followed by immediate fixationHDACi has been reported to revert UAinduced dysfunction of NiemannPick C1 (NPC1) In conclusion, these findings demonstrate that NPC1 plays an important role in type I FCoV infection UA or other cholesterol transport inhibitor may be considered as the antiviral drug for the treatment of cats with FIP
Increased Exosome Secretion In Neurons Aging In Vitro By Npc1 Mediated Endosomal Cholesterol Buildup Life Science Alliance
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A part of these mutant NPC1 proteins expressed in NPC1(−) cells was localized on CTBlabeled vesicles UA treatment of "knock in" cells NPC1(−) cells that stably expressed wildtype NPC1 caused CTB accumulation similar to that in NPC1(−) cells, and a part of wildtype NPC1was localized on CTBlabeled vesicles in drugtreated cells UA inhibits outward movements of NPC1 organelles, trapping membranes and cholesterol in perinuclear organelles similar to those in NPC1mutant cells, even when cells are grown in lipoproteindepleted serumMutations cause Niemann–Pick type C disease NPC1 contains a "sterolsensing domain" (SSD) that also appears in several key regulatory proteins of cholesterol biosynthesis, uptake, and signaling
Simultaneous Targeting Of Npc1 And Vdac1 By Itraconazole Leads To Synergistic Inhibition Of Mtor Signaling And Angiogenesis Abstract Europe Pmc
Plos Genetics Cell Autonomous Death Of Cerebellar Purkinje Neurons With Autophagy In Niemann Pick Type C Disease
NPC1 / HeLa cells were transfected with GFPmouse NPC1wild type or P251C/L929C plasmids for 48 h Thirtytwo hours post transfection, cells were incubated with 1 mM Ua for 16 h; Distribution of NPC1 in UAtreated CHO/NPC1 cells On day 0, CHO/NPC1 cells were plated in medium A and incubated with 2 μg/ml UA On day 1, cells were incubated with 5 μ m LysoSensor Green DND153 for 2 h before fixation and stained for NPC1 (A) and filipin (B) Acidic organelles were visualized using the LysoSensor probe (C Ua was not present during the basal period (DMEM, Glutamax, 02% BSA) Incubations with the LXR agonist GW3965 at 10 µM (SigmaAldrich) were performed during the final 16 h of 72 h Ua treatment Control (K1) and NPC1 knockout (2–2) CHO cells were a kind gift from Dr Andrew Brown (UNSW, Sydney, Australia)
Npc1 Regulates The Distribution Of Phosphatidylinositol 4 Kinases At Golgi And Lysosomal Membranes The Embo Journal
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
Baculovirus Utilizes Cholesterol Transporter Niemann Pick C1 For Host Cell Entry Biorxiv
A Trimeric Rab7 Gef Controls Npc1 Dependent Lysosomal Cholesterol Export Nature Communications
Simultaneous Targeting Of Npc1 And Vdac1 By Itraconazole Leads To Synergistic Inhibition Of Mtor Signaling And Angiogenesis Abstract Europe Pmc
Adenosine a Receptor Stimulation Restores Cell Functions And Differentiation In Niemann Pick Type C Like Oligodendrocytes Scientific Reports
Npc Intracellular Cholesterol Transporter 1 Npc1 Mediated Cholesterol Export From Lysosomes Journal Of Biological Chemistry
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
Plos One Late Endosomal Cholesterol Accumulation Leads To Impaired Intra Endosomal Trafficking
Figure 3 From Npc1 Intracellular Cholesterol Trafficking And Atherosclerosis Semantic Scholar
Figure 8 From Cholesterol Depletion Corrects App And Bace1 Misstrafficking In Npc1 Deficient Cells Semantic Scholar
Inhibition Of Npc1 Repressed Insulin Stimulated Glucose Uptake A Download Scientific Diagram
The Intracellular Cholesterol Transport Inhibitor Ua Inhibits The Exosome Dependent Release Of Mature Hepatitis C Virus Journal Of Virology
Ua Causes Accumulation Of Cholesterol In The Late Download Scientific Diagram
Npc1
Inter Domain Dynamics Drive Cholesterol Transport By Npc1 And Npc1l1 Proteins Biorxiv
Inhibition Of Ldl Cholesterol Esterification By Gw707 And Ua Cho Download Scientific Diagram
Ijms Free Full Text Adenovirus Reveals New Pathway For Cholesterol Egress From The Endolysosomal System Html
Journal Of Lipid Research Same Reference The Drug Ua Which Inhibits Npc1 And Mimics The Npc Lysosomal Storage Phenotype Inhibits Replication Of Hiv Strains Seemingly Independent Of Their Tropism If
Plos One Loss Of Cathepsin B And L Leads To Lysosomal Dysfunction Npc Like Cholesterol Sequestration And Accumulation Of The Key Alzheimer S Proteins
Impaired Antibacterial Autophagy Links Granulomatous Intestinal Inflammation In Niemann Pick Disease Type C1 And Xiap Deficiency With Nod2 Variants In Crohn S Disease Gut
Increased Exosome Secretion In Neurons Aging In Vitro By Npc1 Mediated Endosomal Cholesterol Buildup Life Science Alliance
The Cytosolic Adaptor Ap 1a Is Essential For The Trafficking And Function Of Niemann Pick Type C Proteins Poirier 13 Traffic Wiley Online Library
Effect Of Ua On Free Cholesterol Neutral Lipid And Npc1 Download Scientific Diagram
Lipids On Trial The Search For The Offending Metabolite In Niemann Pick Type C Disease Lloyd Evans 10 Traffic Wiley Online Library
Multiple Cationic Amphiphiles Induce A Niemann Pick C Phenotype And Inhibit Ebola Virus Entry And Infection
Acid Ceramidase Improves Mitochondrial Function And Oxidative Stress In Niemann Pick Type C Disease By Repressing Stard1 Expression And Mitochondrial Cholesterol Accumulation Sciencedirect
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
Role Of Cathepsin D In Ua Induced Neuronal Cell Death Journal Of Biological Chemistry
A Trimeric Rab7 Gef Controls Npc1 Dependent Lysosomal Cholesterol Export Biorxiv
Activation Of Pkc Triggers Rescue Of Npc1 Patient Specific Ipsc Derived Glial Cells From Gliosis Orphanet Journal Of Rare Diseases Full Text
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Niemann Pick C1 Is Essential For Ebolavirus Replication And Pathogenesis In Vivo Mbio
Structural Basis For Itraconazole Mediated Npc1 Inhibition Nature Communications
The Cholesterol Transport Inhibitor Ua Inhibits Type I Feline Coronavirus Infection Sciencedirect
Ijms Free Full Text Impaired Retromer Function In Niemann Pick Type C Disease Is Dependent On Intracellular Cholesterol Accumulation Html
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
Characterization Of Fluorescent Sterol Binding To Purified Human Npc1 Journal Of Biological Chemistry
Dynamic Movements Of Organelles Containing Niemann Pick C1 Protein Npc1 Involvement In Late Endocytic Events Molecular Biology Of The Cell
3 3 A Structure Of Niemann Pick C1 Protein Reveals Insights Into The Function Of The C Terminal Luminal Domain In Cholesterol Transport Pnas
Ua Inhibits Classical Swine Fever Virus Replication Through Interference With Intracellular Cholesterol Trafficking Sciencedirect
Frontiers Baculovirus Utilizes Cholesterol Transporter Niemann Pick C1 For Host Cell Entry Microbiology
Ijms Free Full Text Understanding And Treating Niemann Pick Type C Disease Models Matter Html
Visualisation Of Cholesterol And Ganglioside Gm1 In Zebrafish Models Of Niemann Pick Type C Disease And Smith Lemli Opitz Syndrome Using Light Sheet Microscopy Springerlink
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Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
Drug Induced Increase In Lysobisphosphatidic Acid Reduces The Cholesterol Overload In Niemann Pick Type C Cells And Mice Embo Reports
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Structure Of Human Niemann Pick C1 Protein Pnas
Structural Insights Into The Niemann Pick C1 Npc1 Mediated Cholesterol Transfer And Ebola Infection Sciencedirect
Inhibition Of Intracellular Cholesterol Transport Alters Presenilin Localization And Amyloid Precursor Protein Processing In Neuronal Cells Journal Of Neuroscience
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
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Effects Of Ua And Progesterone Treatment On Npc1 Expression In Download Scientific Diagram
Increased Exosome Secretion In Neurons Aging In Vitro By Npc1 Mediated Endosomal Cholesterol Buildup Life Science Alliance
A Trimeric Rab7 Gef Controls Npc1 Dependent Lysosomal Cholesterol Export Nature Communications
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Suppression Of Macrophage Eicosanoid Synthesis By Atherogenic Lipoproteins Is Profoundly Affected By Cholesterol Fatty Acyl Esterification And The Niemann Pick C Pathway Of Lipid Trafficking Journal Of Biological Chemistry
Plos One The Role Of The Niemann Pick Disease Type C1 Protein In Adipocyte Insulin Action
Association Of Autophagy With Cholesterol Accumulated Compartments In Niemann Pick Disease Type C Cells Journal Of Clinical Neuroscience
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Niemann Pick C1 Functions In Regulating Lysosomal Amine Content Sciencedirect
Journal Of Lipid Research Same Reference The Drug Ua Which Inhibits Npc1 And Mimics The Npc Lysosomal Storage Phenotype Inhibits Replication Of Hiv Strains Seemingly Independent Of Their Tropism If
Increased Exosome Secretion In Neurons Aging In Vitro By Npc1 Mediated Endosomal Cholesterol Buildup Life Science Alliance
3 3 A Structure Of Niemann Pick C1 Protein Reveals Insights Into The Function Of The C Terminal Luminal Domain In Cholesterol Transport Pnas
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Jstor Org
Cells Free Full Text Cholesterol Trafficking An Emerging Therapeutic Target For Angiogenesis And Cancer Html
Adenosine a Receptor Stimulation Restores Cell Functions And Differentiation In Niemann Pick Type C Like Oligodendrocytes Scientific Reports
Frontiers Intracellular Cholesterol Trafficking And Impact In Neurodegeneration Molecular Neuroscience
Identification Of Npc1 As The Target Of Ua An Inhibitor Of Lysosomal Cholesterol Export And Ebola Infection Elife
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Dynamic Movements Of Organelles Containing Niemann Pick C1 Protein Npc1 Involvement In Late Endocytic Events Molecular Biology Of The Cell
Extracellular Vesicles Lipids As Key Components Of Their Biogenesis And Functions Journal Of Lipid Research
Triazoles Inhibit Cholesterol Export From Lysosomes By Binding To Npc1 Pnas
Human Wt Fibroblasts With Or Without Ua Treatment And Download Scientific Diagram
Fluorescent Micrograph Of Fibroblasts From Ua Treated Fibroblasts Download Scientific Diagram
Identifying The Key Events Behind Niemann Pick Type C1 Disease Pathology Cholesterol For Once Is Not A Killer Emyr Lloyd Evans Ppt Download
