Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation
Niemann-Pick disease type C (NPC), caused by mutations in the NPC1 gene or the NPC2 gene, is characterized by the accumulation of unesterified cholesterol and other lipids in endo/lysosomal compartments. NPC2 is a small, soluble, lysosomal protein that is targeted to this compartment via a mannose 6...
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doaj-5492a1c95f574b3c9c5cc2e59c4f4d9d2021-04-27T04:43:19ZengElsevierJournal of Lipid Research0022-22752005-12-01461225592569Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulationMarion Willenborg0Christine Kathrin Schmidt1Peter Braun2Jobst Landgrebe3Kurt von Figura4Paul Saftig5Eeva-Liisa Eskelinen6Institute of Biochemistry, University of Kiel, D-24098 Kiel, GermanyInstitute of Biochemistry, University of Kiel, D-24098 Kiel, GermanyInstitute of Biochemistry 2, University of Göttingen, D-37075 Göttingen, GermanyInstitute of Biochemistry 2, University of Göttingen, D-37075 Göttingen, GermanyInstitute of Biochemistry 2, University of Göttingen, D-37075 Göttingen, GermanyInstitute of Biochemistry, University of Kiel, D-24098 Kiel, GermanyTo whom correspondence should be addressed.; Institute of Biochemistry, University of Kiel, D-24098 Kiel, Germany; Division of Biochemistry, Department of Biological and Environmental Sciences, FI-00014 University of Helsinki, Helsinki, FinlandNiemann-Pick disease type C (NPC), caused by mutations in the NPC1 gene or the NPC2 gene, is characterized by the accumulation of unesterified cholesterol and other lipids in endo/lysosomal compartments. NPC2 is a small, soluble, lysosomal protein that is targeted to this compartment via a mannose 6-phosphate-inhibitable pathway. To obtain insight into the roles of mannose 6-phosphate receptors (MPRs) in NPC2 targeting, we here examine the trafficking and function of NPC2 in fibroblast lines deficient in one or both of the two MPRs, MPR46 and MPR300. We demonstrate that either MPR alone is sufficient to transport NPC2 to the endo/lysosomal compartment, although MPR300 seems to be more efficient than MPR46. In the absence of both MPRs, NPC2 is secreted into the culture medium, and only a small amount of intracellular NPC2 can be detected, mainly in the endoplasmic reticulum. This leads to massive accumulation of unesterified cholesterol in the endo/lysosomal compartment of the MPR46/300-deficient fibroblasts, a phenotype similar to that of the NPC patient fibroblasts. In addition, we observed an upregulation of NPC1 protein and mRNA in the MPR-double-deficient cells.Taken together, our results suggest that the lysosomal targeting of NPC2 is strictly dependent on MPRs in fibroblasts.http://www.sciencedirect.com/science/article/pii/S0022227520328431NPC1NPC2cholesterollate endosome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marion Willenborg Christine Kathrin Schmidt Peter Braun Jobst Landgrebe Kurt von Figura Paul Saftig Eeva-Liisa Eskelinen |
spellingShingle |
Marion Willenborg Christine Kathrin Schmidt Peter Braun Jobst Landgrebe Kurt von Figura Paul Saftig Eeva-Liisa Eskelinen Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation Journal of Lipid Research NPC1 NPC2 cholesterol late endosome |
author_facet |
Marion Willenborg Christine Kathrin Schmidt Peter Braun Jobst Landgrebe Kurt von Figura Paul Saftig Eeva-Liisa Eskelinen |
author_sort |
Marion Willenborg |
title |
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation |
title_short |
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation |
title_full |
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation |
title_fullStr |
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation |
title_full_unstemmed |
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation |
title_sort |
mannose 6-phosphate receptors, niemann-pick c2 protein, and lysosomal cholesterol accumulation |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2005-12-01 |
description |
Niemann-Pick disease type C (NPC), caused by mutations in the NPC1 gene or the NPC2 gene, is characterized by the accumulation of unesterified cholesterol and other lipids in endo/lysosomal compartments. NPC2 is a small, soluble, lysosomal protein that is targeted to this compartment via a mannose 6-phosphate-inhibitable pathway. To obtain insight into the roles of mannose 6-phosphate receptors (MPRs) in NPC2 targeting, we here examine the trafficking and function of NPC2 in fibroblast lines deficient in one or both of the two MPRs, MPR46 and MPR300. We demonstrate that either MPR alone is sufficient to transport NPC2 to the endo/lysosomal compartment, although MPR300 seems to be more efficient than MPR46. In the absence of both MPRs, NPC2 is secreted into the culture medium, and only a small amount of intracellular NPC2 can be detected, mainly in the endoplasmic reticulum. This leads to massive accumulation of unesterified cholesterol in the endo/lysosomal compartment of the MPR46/300-deficient fibroblasts, a phenotype similar to that of the NPC patient fibroblasts. In addition, we observed an upregulation of NPC1 protein and mRNA in the MPR-double-deficient cells.Taken together, our results suggest that the lysosomal targeting of NPC2 is strictly dependent on MPRs in fibroblasts. |
topic |
NPC1 NPC2 cholesterol late endosome |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520328431 |
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