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Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C–related protein reveals a primordial role in subcellular sphingolipid distribution

¹ Institute of Human Nutrition, Columbia University Medical Center, New York, NY 10032
² Department of Pharmacology, Columbia University Medical Center, New York, NY 10032
³ Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032
⁴ Department of Pediatrics, Columbia University Medical Center, New York, NY 10032
⁵ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Dr. S.L. Sturley, Institute of Human Nutrition, Columbia University Medical Center, 630 W. 168 St., New York, NY 10032. Tel: (212) 305-6304. Fax: (212) 305-3079. email: sls37{at}columbia.edu

Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C–related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.

Key Words: transport; vacuole; lysosome; ceramide; neurodegeneration

K. Malathi's present address is Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.

K. Higaki's present address is Research Center for Bioscience and Technology, Tottori University, Japan.

Abbreviations used in this paper: ABA, aureobasidin A; DHS, dihydrosphingosine; E–L, endosomal–lysosomal; IPC, inositolphosphorylceramide; LDL, low density lipoprotein; MIPC, mannosyl-IPC; M(IP)₂C, mannosyl-di-IPC; NP-C, Niemann Pick type C; NPC1, NP-C gene 1; NCR1, NP-C–related gene 1; SCAP, SREBP cleavage-activating protein; SREBP, sterol regulatory element-binding protein; SSD, sterol-sensing domain.

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