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J. Biol. Chem., Vol. 279, Issue 46, 48214-48223, November 12, 2004

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Targeting of NPC1 to Late Endosomes Involves Multiple Signals, Including One Residing within the Putative Sterol-sensing Domain^*

Catherine Scott, Maureen E. Higgins, Joanna P. Davies, and Yiannis A. Ioannou

From the Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029

The NPC1 protein is a multipass transmembrane protein whose deficiency causes the autosomal recessive lipid storage disorder Niemann-Pick type C1. NPC1 localizes predominantly to late endosomes and has a dileucine motif located within a small cytoplasmic tail thought to target the protein to this location. Our data have suggested previously that the protein can reach its correct location in the absence of its cytoplasmic tail, suggesting that other signals contribute to NPC1 targeting. By using various FLAG-tagged and CD32-NPC1 chimeric fusion constructs, we show that multiple signals are responsible for the trafficking of NPC1 to the endosomal compartment, including the dileucine motif and a previously unidentified signal residing within the putative sterol-sensing domain transmembrane domain 3. Neither region alone was capable of directing heterologous CD32 fusions to late endosomes exclusively via the trans-Golgi network to the late endosome route taken by wild-type NPC1; transmembrane domain 3 was unable to maintain CD32 in late endosomes, indicating that two or more signals work in concert to target and retain NPC1 in this compartment. In addition we confirm that the tail dileucine motif is not essential for NPC1 targeting to late endosomes, and we discuss the implications of this finding along with the previously unappreciated role for transmembrane domain 3 in NPC1 localization and function.

Received for publication, June 1, 2004 , and in revised form, August 6, 2004.

^* This work was supported by National Institutes of Health Grants RO1 DK065793 and RO1 DK54736 and by a grant from the March of Dimes Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Human Genetics, Box 1498, Mount Sinai School of Medicine, Fifth Ave. at 100th St., New York, NY 10029. Tel.: 212-659-6720; Fax: 212-348-3605; E-mail: yiannis.ioannou{at}mssm.edu.

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