期刊
JOURNAL OF CELL SCIENCE
卷 120, 期 20, 页码 3640-3652出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03487
关键词
Niemann-Pick disease Type C; NPC1; NPC2; AP-3; endosomal trafficking
类别
资金
- NIAMS NIH HHS [2T32AR007587-11] Funding Source: Medline
- NIGMS NIH HHS [GM 077569] Funding Source: Medline
- NINDS NIH HHS [NS42599, NS044743, NS40564] Funding Source: Medline
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 NPC 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.
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