NPC1-Containing Compartment of Human Granulosa-Lutein Cells: A Role in the Intracellular Trafficking of Cholesterol Supporting Steroidogenesis

Watari, Hidemichi; Blanchette‐Mackie, E. Joan; Dwyer, Nancy K.; Sun, Gwo-Shing; Glick, Jane M.; Patel, Seema; Neufeld, Edward B.; Pentchev, Peter G.; Strauss, Jerome F.

doi:10.1006/excr.1999.4774

Cited by 47 publications

(32 citation statements)

References 34 publications

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“…NPC1 protein synthesized in the endoplasmic reticulum moves to the Golgi apparatus for processing of its N-linked oligosaccharides (6). Our study on living cells shows an accumulation of NPC1-GFP in the endoplasmic reticulum network within 12 h after transfection; NPC1-GFP then appears in tiny vesicles dispersed among cisternal elements of the endoplasmic reticulum within 17 h of transfection (Fig.…”

Section: Translocation Of Npc1-gfp From Site Of Synthesis In Endoplasmentioning

confidence: 60%

“…The cDNA encoding human NPC1 corrects the defect in NPC1 mutant cells and facilitates clearance of the extensive lysosomal pools of cholesterol (2,5). After biosynthesis of NPC1 in the endoplasmic reticulum, the protein is processed further in the Golgi apparatus (6); at steady state, it is associated with late endosomes. Cellular cholesterol enrichment, through endocytic uptake of low-density lipoprotein (LDL), alters the intracellular distribution of NPC1 protein from a finely dispersed granular pattern to sequestration in prominent cytoplasmic vesicles (7,8).…”

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confidence: 99%

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Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease

Zhang

Dwyer²,

Love³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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130

126

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Niemann-Pick type C1 (NPC1) disease results from a defect in the NPC1 protein and is characterized by a pathological accumulation of cholesterol and glycolipids in endocytic organelles. We followed the biosynthesis and trafficking of NPC1 with the use of a functional green fluorescent protein-fused NPC1. Newly synthesized NPC1 is exported from the endoplasmic reticulum and requires transit through the Golgi before it is targeted to late endosomes. NPC1-containing late endosomes then move by a dynamic process involving tubulation and fission, followed by rapid retrograde and anterograde migration along microtubules. Cell fusion studies with normal and mutant NPC1 cells show that exchange of contents between late endosomes and lysosomes depends upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement requires an intact NPC1 sterol-sensing domain and is retarded by an elevated endosomal cholesterol content. We conclude that the neuropathology and cellular lysosomal lipid accumulation in NPC1 disease results, at least in part, from striking defects in late endosomal tubulovesicular trafficking. D efects of the NPC1 gene cause a severe endocytic accumulation of cholesterol in a variety of cellular and animal models of Niemann-Pick C1 (NPC1) disease (1, 2). The fatal damage in NPC1 disease is neurodegeneration starting from early life. The product of the NPC1 gene (NPC1) is composed of 1,278 aa and is predicted to contain 13 transmembrane domains (2, 3). NPC1 possesses a sterol-sensing domain (SSD) that is also found in two other proteins critical to maintaining cellular cholesterol homeostasis, the sterol response elementbinding protein cleavage-activating protein and the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (2, 4). The cDNA encoding human NPC1 corrects the defect in NPC1 mutant cells and facilitates clearance of the extensive lysosomal pools of cholesterol (2, 5). After biosynthesis of NPC1 in the endoplasmic reticulum, the protein is processed further in the Golgi apparatus (6); at steady state, it is associated with late endosomes. Cellular cholesterol enrichment, through endocytic uptake of low-density lipoprotein (LDL), alters the intracellular distribution of NPC1 protein from a finely dispersed granular pattern to sequestration in prominent cytoplasmic vesicles (7,8). These NPC1-containing vesicles are positive for lysosomal-associated membrane protein 2 (LAMP2) (7, 9), are not enriched in lysosomal hydrolases (7), and are positive for the late endosomal marker proteins Rab7 (7) and Rab 9 (10). NPC1-containing late endosomes are critical for the retroendocytic trafficking of multiple lysosomal cargo (4, 9). Retroendocytic clearance of fluid phase markers, such as sucrose, from late endosomes is retarded by LDL-derived cellular enrichment of cholesterol (9). We have recently shown that cholesterol modulates glycolipid sorting from NPC1-containing late endosomes into lysosomes (7). In this report, we have visualized functional green fluorescent protein-labeled...

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Section: Translocation Of Npc1-gfp From Site Of Synthesis In Endoplasmentioning

confidence: 60%

mentioning

confidence: 99%

Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease

Zhang

Dwyer²,

Love³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

130

126

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“…Thus, the intracellular cholesterol-rich domain visualized by BC staining significantly colocalized with the compartment(s) that contains the NPC1-GFP in U18666A-treated cells. Previously, Strauss, Blanchette-Mackie, and colleagues, who used filipin as the intracellular cholesterol stain (49), made the same observation. It has been suggested that U18666A creates the NPC-like phenotype by "freezing" the NPC1 protein on the surface of cholesterolladen lysosomes (47).…”

Section: Effect Of Npc1 Expression On Intracellular Bc Staining Of Ctmentioning

confidence: 61%

Biotinylated θ-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells

Sugii

Reid

Ohgami

et al. 2003

Journal of Lipid Research

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“…Previous studies have shown that when NPC1 loses functional capacity in cells, it is typically overexpressed to compensate for the reduced activity Watari et al, 2000). Therefore, we comparatively evaluated NPC1 RNA and protein levels in drug-sensitive and MDR HL-60 cells.…”

Section: Resultsmentioning

confidence: 99%

Niemann-Pick C1 Protein Facilitates the Efflux of the Anticancer Drug Daunorubicin from Cells According to a Novel Vesicle-Mediated Pathway

Gong¹,

Duvvuri²,

Duncan³

et al. 2005

J Pharmacol Exp Ther

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Niemann-Pick C1 (NPC1) is a late endosomal/lysosomal membrane protein originally reported on for its role in cholesterol trafficking in mammalian cells. NPC1 has been shown recently to share significant structural homology with a family of prokaryotic permeases and was proposed to play a role in intracellular drug transport; however, the mechanism for this has not been fully understood. We provide evidence here that is consistent with NPC1's involvement in a vesicle-mediated clearance of the anticancer agent daunorubicin from cells. In experiments with human fibroblasts, we demonstrate that lysosomal efflux of daunorubicin, as well as dextran molecules, are significantly reduced in cells with mutated and dysfunctional NPC1 compared with wild-type fibroblasts. Furthermore, we show that NPC1 is implicated in a lysosomal drug sequestration phenotype exhibited by the multidrug-resistant (MDR) human leukemic HL-60 cancer cell line. Evaluations of cholesterol trafficking, NPC1 mRNA levels, and protein expression are all consistent with a loss of NPC1 activity that is associated with the emergence of the MDR phenotype in this cell line. Collectively, this work proposes a novel role for NPC1 in a vesiclemediated pathway responsible for the clearance of drugs from cells and provides an explanation for a drug sequestration phenotype exhibited by the MDR HL-60 cell line.

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NPC1-Containing Compartment of Human Granulosa-Lutein Cells: A Role in the Intracellular Trafficking of Cholesterol Supporting Steroidogenesis

Cited by 47 publications

References 34 publications

Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease

Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease

Biotinylated θ-toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells

Niemann-Pick C1 Protein Facilitates the Efflux of the Anticancer Drug Daunorubicin from Cells According to a Novel Vesicle-Mediated Pathway

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