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Journal of Lipid Research, Vol. 46, 2559-2569, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation

Marion Willenborg^*, Christine Kathrin Schmidt^*, Peter Braun, Jobst Landgrebe, Kurt von Figura, Paul Saftig^1,* and Eeva-Liisa Eskelinen^1,2,*,

^* Institute of Biochemistry, University of Kiel, D-24098 Kiel, Germany
Institute of Biochemistry 2, University of Göttingen, D-37075 Göttingen, Germany
Division of Biochemistry, Department of Biological and Environmental Sciences, FI-00014 University of Helsinki, Helsinki, Finland

Published, JLR Papers in Press, September 21, 2005. DOI 10.1194/jlr.M500131-JLR200

¹ P. Saftig and E-L. Eskelinen contributed equally to this work.

² To whom correspondence should be addressed. e-mail Eeva-Liisa.Eskelinen{at}Helsinki.Fi

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.

Abbreviations: BMP, bis(monoacylglycero)phosphate; endo H, endoglycosidase H; ER, endoplasmic reticulum; MEF, mouse embryonic fibroblast; MPR, mannose 6-phosphate receptor; NPC, Niemann-Pick type C; PNGase F, peptide N-glycosidase F; TGN, trans Golgi network

Supplementary key words NPC1 • NPC2 • cholesterol • late endosome

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