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Vol. 12, Issue 3, 601-614, March 2001
Departments of Developmental Biology and Genetics, Howard Hughes
Medical Institute, Beckman Center B300, Stanford University School of
Medicine, Stanford, California 94305
People homozygous for mutations in the Niemann-Pick type C1
(NPC1) gene have physiological defects, including excess
accumulation of intracellular cholesterol and other lipids, that lead
to drastic neural and liver degeneration. The NPC1 multipass
transmembrane protein is resident in late endosomes and lysosomes, but
its functions are unknown. We find that organelles containing
functional NPC1-fluorescent protein fusions undergo dramatic movements,
some in association with extending strands of endoplasmic reticulum. In
NPC1 mutant cells the NPC1-bearing organelles that
normally move at high speed between perinuclear regions and the
periphery of the cell are largely absent. Pulse-chase experiments with
dialkylindocarbocyanine low-density lipoprotein showed that NPC1
organelles function late in the endocytic pathway; NPC1 protein may aid
the partitioning of endocytic and lysosomal compartments. The close
connection between NPC1 and the drug U18666A, which causes NPC1-like
organelle defects, was established by rescuing drug-treated cells with
overproduced NPC1. U18666A inhibits outward movements of NPC1
organelles, trapping membranes and cholesterol in perinuclear
organelles similar to those in NPC1 mutant cells, even
when cells are grown in lipoprotein-depleted serum. We conclude that
NPC1 protein promotes the creation and/or movement of particular late
endosomes, which rapidly transport materials to and from the cell periphery.
Online version of this article
contains video material for Figure 2-4, 7, and 8. Online version
available at www.molbiolcell.org.
*
Corresponding author. E-mail address:
scott{at}cmgm.stanford.edu.
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