JCB logo
Accuri Cytometers
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 17 February 2004. doi:10.1083/jcb.200310046
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 4, 547-556
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 486K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Malathi, K.
Right arrow Articles by Sturley, S. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Malathi, K.
Right arrow Articles by Sturley, S. L.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*Protein
*Substance via MeSH
Related Collections
Right arrowRelated Article
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Article

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

Krishnamurthy Malathi1, Katsumi Higaki1, Arthur H. Tinkelenberg1, Dina A. Balderes1, Dorca Almanzar-Paramio2, Lisa J. Wilcox1, Naz Erdeniz3, Francis Redican1, Mahajabeen Padamsee1, Ying Liu1, Sohail Khan1, Frederick Alcantara1, Eugene D. Carstea5, Jill A. Morris5, and Stephen L. Sturley1,4

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 and K. Higaki contributed equally to this work.

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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?

Related Article

A primordial mover for sphingolipids
Alan W. Dove
J. Cell Biol. 2004 164: 476. [Full Text] [PDF]



This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents