Niemann–Pick Type C Mutations Cause Lipid Traffic Jam

Liscum, Laura

doi:10.1034/j.1600-0854.2000.010304.x

Cited by 141 publications

(118 citation statements)

References 60 publications

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“…Mammalian NPC1 and NPC2 are hypothesized to function in retrograde lipid transport from late endosomes and lysosomes (Liscum, 2000), suggesting that the localization of NPC1 and NPC2 to these organelles is of primary importance to their function. Unraveling the mechanisms that regulate NP-C protein transport is therefore crucially important to understanding the pathology of the disease.…”

Section: Discussionmentioning

confidence: 99%

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Berger

Salazar

Styers

et al. 2007

Journal of Cell Science

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Niemann-Pick Type C (NP-C) disease, caused by mutations in either human NPC1 (hNPC1) or human NPC2 (hNPC2), is characterized by the accumulation of unesterified cholesterol in late endosomes. Although it is known that the NP-C proteins are targeted to late endosomal/lysosomal compartments, their delivery mechanisms have not been fully elucidated. To identify mechanisms regulating NP-C protein localization, we used Saccharomyces cerevisiae, which expresses functional homologs of both NP-C proteins – scNcr1p and scNpc2p. Targeting of scNcr1p to the vacuole was perturbed in AP-3-deficient yeast cells, whereas the delivery of scNpc2p was affected by deficiencies in either AP-3 or GGA. We focused on the role of the AP-3 pathway in the targeting of the mammalian NP-C proteins. We found that, although mouse NPC1 (mNPC1) and hNPC2 co-localize with AP-3 to a similar extent in fibroblasts, hNPC2 preferentially co-localizes with AP-1. Importantly, the targeting of both mammalian NPC1 and NPC2 is dependent on AP-3. Moreover, and consistent with the NP-C proteins playing a role in cholesterol metabolism, AP-3-deficient cells have reduced levels of cholesterol. These results provide information about how the NP-C proteins are targeted to their sites of action and illustrate the possibility that defective sorting of the NP-C proteins along the endocytic route can alter cellular cholesterol.

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Section: Discussionmentioning

confidence: 99%

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Berger

Salazar

Styers

et al. 2007

Journal of Cell Science

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“…Intracellular cholesterol trafficking has been shown to require two cholesterol binding proteins within the lumen of late endosome and lysosome, the Niemann-Pick disease type C (NPC)1 and NPC2 proteins (24)(25)(26). As their names imply, genetic mutations in either gene have been shown to be associated with the corresponding neurological disease in humans and to cause blockade of intracellular cholesterol trafficking (27,28). To determine whether inhibition of intracellular cholesterol trafficking by alternative means also caused inhibition of the mTOR pathway in endothelial cells, we knocked down NPC1 and NPC2, respectively, using siRNA in HUVECs (Fig.…”

Section: Proper Cholesterol Trafficking Is Essential For Mtor Activatmentioning

confidence: 99%

Cholesterol trafficking is required for mTOR activation in endothelial cells

Xu¹,

Dang²,

Ren³

et al. 2010

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

185

184

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Mammalian target of rapamycin (mTOR) constitutes a nodal point of a signaling network that regulates cell growth and proliferation in response to various environmental cues ranging from growth factor stimulation to nutrients to stress. Whether mTOR is also affected by cholesterol homeostasis, however, has remained unknown. We report that blockade of cholesterol trafficking through lysosome by a newly identified inhibitor of angiogenesis, itraconazole, leads to inhibition of mTOR activity in endothelial cells. Inhibition of mTOR by itraconazole but not rapamycin can be partially restored by extracellular cholesterol delivered by cyclodextrin. Moreover, other known inhibitors of endosomal/lysosomal cholesterol trafficking as well as siRNA knockdown of Niemann–Pick disease type C (NPC) 1 and NPC2 also cause inhibition of mTOR in endothelial cells. In addition, both the accumulation of cholesterol in the lysosome and inhibition of mTOR caused by itraconazole can be reversed by thapsigarin. These observations suggest that mTOR is likely to be involved in sensing membrane sterol concentrations in endothelial cells, and the cholesterol trafficking pathway is a promising target for the discovery of inhibitors of angiogenesis.

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“…By contrast, in fibroblasts from patients with Niemann-Pick type C (NPC) disease, an autosomal recessive neurodegenerative lysosomal lipid storage disease characterized by a late endosomal/lysosomal accumulation of unesterified cholesterol derived from LDLs [reviewed in refs. (17,18)], MPR300 is trapped in a compartment that has accumulated free cholesterol, a late endosomal marker lysobisphosphatidic acid (LBPA), and a late endosome/lysosome marker, LAMP-2 (14). Given the function of MPR300 as the receptor of lysosomal enzymes, such an alteration to its localization may result in the missorting of lysosomal enzymes.…”

mentioning

confidence: 99%

Distribution and trafficking of MPR300 is normal in cells with cholesterol accumulated in late endocytic compartments

Umeda

Fujita

Kuronita

et al. 2003

Journal of Lipid Research

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It has been reported that an accumulation of cholesterol within late endosomes/lysosomes in Niemann-Pick type C (NPC) fibroblasts and U18666A-treated cells causes impairment of retrograde trafficking of the cation-independent mannose 6-phosphate/IGF-II receptor (MPR300) from late endosomes to the trans -Golgi network (TGN). In apparent conflict with these results, here we show that as in normal fibroblasts, MPR300 localizes exclusively to the TGN in NPC fibroblasts as well as in normal fibroblasts treated with U18666A. This localization can explain why several lysosomal properties and functions, such as intracellular lysosomal enzyme activity and localization, the biosynthesis of cathepsin D, and protein degradation, are all normal in NPC fibroblasts. These results, therefore, suggest that the accumulation of cholesterol in late endosomes/lysosomes does not affect the retrieval of MPR300 from endosomes to the TGN. Furthermore, treatment of normal and NPC fibroblasts with chloroquine, which inhibits membrane traffic from early endosomes to the TGN, resulted in a redistribution of MPR300 to EEA1 and internalized transferrin-positive, but LAMP-2-negative, early-recycling endosomes. We propose that in normal and NPC fibroblasts, MPR300 is exclusively targeted from the TGN to early endosomes, from where it rapidly recycles back to the TGN without being delivered to late endosomes. This notion provides important insights into the definition of late endosomes, as well as the biogenesis of lysosomes. Two distinct and related mannose 6-phosphate receptors (MPRs), the cation-dependent mannose 6-phosphate receptor (MPR46) and the cation-independent mannose 6-phosphate/IGF-II receptor (MPR300), are responsible for sorting soluble lysosomal enzymes from the secretory pathway. They have a largely overlapping but apparently distinct affinity for lysosomal enzymes (1, 2). Newly synthesized lysosomal enzymes acquire mannose 6-phosphate residues in the Golgi complex and are recognized in the trans -Golgi network (TGN) by MPRs [reviewed in refs. (3,4)]. The ligand-receptor complex is subsequently packed into clathrin-coated vesicles and targeted to endosomal compartments. The acidic environment of endosomes causes the release of the enzymes from MRPs, after which the lysosomal enzymes are transferred to lysosomes while the MPRs are retrieved to the TGN for further rounds of sorting. Therefore, the MPRs play a key role in the biogenesis and function of lysosomes.Intracellular trafficking of MPRs is mediated by signals present in their cytoplasmic tails, which contain two signals, tyrosine-and dileucine-based sorting signals, as well as by posttranslational modifications, such as the phosphorylation of serine residues and the palmitoylation of cysteine residues (3, 4). Notably, an acidic cluster-dileucine motif that consists of a cluster of acidic amino acid residues followed by dileucine residues is important to the sorting of MPRs from the TGN to endosomes. Recent progress in the study of MPR trafficking from the TGN to e...

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Niemann–Pick Type C Mutations Cause Lipid Traffic Jam

Cited by 141 publications

References 60 publications

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Cholesterol trafficking is required for mTOR activation in endothelial cells

Distribution and trafficking of MPR300 is normal in cells with cholesterol accumulated in late endocytic compartments

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