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First published online 25 September 2007
doi: 10.1242/jcs.03487

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The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Adam C. Berger^1,2,3,*, Gloria Salazar¹, Melanie L. Styers^1,3, Karen A. Newell-Litwa^1,3, Erica Werner¹, Robert A. Maue⁴, Anita H. Corbett² and Victor Faundez^1,

¹ Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
² Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
³ Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University Graduate Division of Biological and Biomedical Sciences, Atlanta, GA 30322, USA
⁴ Departments of Physiology and Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA

Author for correspondence (e-mail: faundez{at}cellbio.emory.edu)

Accepted 13 August 2007

Niemann-Pick Type C (NP-C) disease, caused by mutations in either human NPC1 (hNPC1) or human NPC2 (hNPC2), is characterized by the accumulation of unesterified cholesterol in late endosomes. Although it is known that the NP-C proteins are targeted to late endosomal/lysosomal compartments, their delivery mechanisms have not been fully elucidated. To identify mechanisms regulating NP-C protein localization, we used Saccharomyces cerevisiae, which expresses functional homologs of both NP-C proteins – scNcr1p and scNpc2p. Targeting of scNcr1p to the vacuole was perturbed in AP-3-deficient yeast cells, whereas the delivery of scNpc2p was affected by deficiencies in either AP-3 or GGA. We focused on the role of the AP-3 pathway in the targeting of the mammalian NP-C proteins. We found that, although mouse NPC1 (mNPC1) and hNPC2 co-localize with AP-3 to a similar extent in fibroblasts, hNPC2 preferentially co-localizes with AP-1. Importantly, the targeting of both mammalian NPC1 and NPC2 is dependent on AP-3. Moreover, and consistent with the NP-C proteins playing a role in cholesterol metabolism, AP-3-deficient cells have reduced levels of cholesterol. These results provide information about how the NP-C proteins are targeted to their sites of action and illustrate the possibility that defective sorting of the NP-C proteins along the endocytic route can alter cellular cholesterol.

Key words: Niemann-Pick disease Type C, NPC1, NPC2, AP-3, Endosomal trafficking