scholarly journals The Tetraspanin CD63/lamp3 Cycles between Endocytic and Secretory Compartments in Human Endothelial Cells

2000 ◽  
Vol 11 (5) ◽  
pp. 1829-1843 ◽  
Author(s):  
Toshihide Kobayashi ◽  
Ulrich M. Vischer ◽  
Corinne Rosnoblet ◽  
Cécile Lebrand ◽  
Margaret Lindsay ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Late Endosome ◽  
Human Endothelial Cells ◽  
Late Endosomes ◽  
Lysobisphosphatidic Acid ◽  
Type C ◽  
Niemann Pick ◽  
Tetraspanin Cd63

In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular–multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel–Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel–Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel–Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel–Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel–Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel–Palade bodies.

scholarly journals Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

2019 ◽  
Vol 77 (14) ◽  
pp. 2839-2857 ◽  
Author(s):  
Elsa Meneses-Salas ◽  
Ana García-Melero ◽  
Kristiina Kanerva ◽  
Patricia Blanco-Muñoz ◽  
Frederic Morales-Paytuvi ◽  
...  
Keyword(s):  
Late Endosome ◽  
Dependent Manner ◽  
Lipid Transfer ◽  
Cholesterol Accumulation ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Membrane Contact ◽  
Domain 3 ◽  
Niemann Pick ◽  
Mutant Cells

Abstract Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.

scholarly journals Evidence that agonists stimulate bivalent-cation influx into human endothelial cells

1988 ◽  
Vol 255 (1) ◽  
pp. 179-184 ◽  
Author(s):  
T J Hallam ◽  
R Jacob ◽  
J E Merritt
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Umbilical Vein ◽  
Free Calcium ◽  
Human Endothelial Cells ◽  
Bivalent Cation ◽  
Human Umbilical Vein ◽  
Fura 2 ◽  
Bivalent Cations ◽  
Umbilical Vein Endothelial Cells

Human umbilical-vein endothelial cells stimulated with thrombin or histamine show an increase in [Ca2+]i (cytoplasmic free calcium concn.) that is maintained well above the basal pre-stimulated value as long as agonist and a source of extracellular Ca2+ are present. These results provide circumstantial evidence that agonists stimulate influx of Ca2+ across the plasma membrane and into the cytoplasm. Here, we have used Mn2+ as the extracellular bivalent cation which can bind to the fluorescent Ca2+ indicator fura-2 to quench its fluorescence completely. Human umbilical-vein endothelial cells were loaded with fura-2 and, in the presence of extracellular Mn2+, thrombin and histamine were shown to cause quenching of the intracellular dye. This result demonstrates conclusively that agonists can stimulate the influx of bivalent cations. Stimulated discharge of Ca2+ from intracellular stores and influx of Mn2+ were temporally resolved in the same cells to show that release of Ca2+ from intracellular stores clearly precedes influx. Influx of Mn2+ was also demonstrated when extracellular Mn2+ was added after agonist at a time when [Ca2+]i had fallen back to the basal value, showing that influx is not dependent on elevated [Ca2+]i.

scholarly journals Intracellular sphingosine releases calcium from lysosomes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Doris Höglinger ◽  
Per Haberkant ◽  
Auxiliadora Aguilera-Romero ◽  
Howard Riezman ◽  
Forbes D Porter ◽  
...  
Keyword(s):  
Calcium Release ◽  
Pore Channel ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Sphingosine 1 Phosphate ◽  
Transcription Factor Eb ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease ◽  
Er Calcium

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

A rare cause of fatal pulmonary alveolar proteinosis: Niemann-Pick disease type C2 and a novel mutation

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Ayhan Yaman ◽  
Fatma T. Eminoğlu ◽  
Tanıl Kendirli ◽  
Çağlar Ödek ◽  
Serdar Ceylaner ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Disease Type ◽  
Neurological Dysfunction ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Type C ◽  
Alveolar Proteinosis ◽  
Niemann Pick ◽  
Pick Disease

AbstractNiemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is

scholarly journals ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice

2014 ◽  
Vol 47 (2) ◽  
pp. 35-43 ◽  
Author(s):  
Masashi Kamikawa ◽  
XiaoFeng Lei ◽  
Yukio Fujiwara ◽  
Kazuchika Nishitsuji ◽  
Hiroshi Mizuta ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Late Endosomes ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick

scholarly journals Cultured human endothelial cells synthesize a plasma membrane protein complex immunologically related to the platelet glycoprotein IIb/IIIa complex

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1176-1180 ◽  
Author(s):  
OC Leeksma ◽  
J Zandbergen-Spaargaren ◽  
JC Giltay ◽  
JA van Mourik
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Endothelial Cell ◽  
Membrane Protein ◽  
Protein Complex ◽  
Platelet Glycoprotein ◽  
Plasma Membrane Protein ◽  
Human Endothelial Cells ◽  
Membrane Protein Complex ◽  
Crossed Immunoelectrophoresis

Abstract We have previously demonstrated that endothelial cells synthesize a plasma membrane protein indistinguishable from platelet glycoprotein (GP) IIa. The present study provides evidence for a further analogy between the platelet and the endothelial cell membrane by showing that cultured endothelial cells also synthesize a membrane protein complex immunologically related to the platelet GP IIb/GP IIIa complex. This evidence is based on the following observations: (1) C17, a murine monoclonal antiplatelet GP IIIa antibody, consistently precipitates two proteins, apparent molecular weights, respectively, 115,000 and 125,000 reduced and 95,000 and 135,000 nonreduced, from metabolically (35S- methionine) as well as surface 125I-labeled cultured human endothelial cells; (2) upon crossed immunoelectrophoresis of solubilized endothelial cells against a polyclonal rabbit antiplatelet antiserum and 125I-labeled C17 IgG, a single precipitate of the protein(s) recognized by C17 is observed. As judged by their mobility in 9% polyacrylamide gels, both endothelial proteins appear to have a somewhat larger molecular weight than their platelet counterparts. Patterns obtained by crossed immunoelectrophoresis are also indicative of a difference in electrophoretic behavior of the platelet GP IIb/IIIa complex and the endothelial cell protein complex.

scholarly journals Lipid–Protein Interactions in Niemann–Pick Type C Disease: Insights from Molecular Modeling

2019 ◽  
Vol 20 (3) ◽  
pp. 717 ◽  
Author(s):  
Simon Wheeler ◽  
Ralf Schmid ◽  
Dan J Sillence
Keyword(s):  
Protein Interactions ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Late Endosomes ◽  
Type C ◽  
Transient Receptor ◽  
Niemann Pick ◽  
Lipid Protein Interactions ◽  
Protein Attachment ◽  
Accumulation Of Lipids

The accumulation of lipids in the late endosomes and lysosomes of Niemann–Pick type C disease (NPCD) cells is a consequence of the dysfunction of one protein (usually NPC1) but induces dysfunction in many proteins. We used molecular docking to propose (a) that NPC1 exports not just cholesterol, but also sphingosine, (b) that the cholesterol sensitivity of big potassium channel (BK) can be traced to a previously unappreciated site on the channel’s voltage sensor, (c) that transient receptor potential mucolipin 1 (TRPML1) inhibition by sphingomyelin is likely an indirect effect, and (d) that phosphoinositides are responsible for both the mislocalization of annexin A2 (AnxA2) and a soluble NSF (N-ethylmaleimide Sensitive Fusion) protein attachment receptor (SNARE) recycling defect. These results are set in the context of existing knowledge of NPCD to sketch an account of the endolysosomal pathology key to this disease.

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