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J Cell Biol. 2011 Jan 10;192(1):121-35. doi: 10.1083/jcb.201004142.

A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking.

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1
School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, New South Wales, Australia.

Abstract

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large and evolutionarily conserved family of lipid-binding proteins that target organelle membranes to mediate sterol signaling and/or transport. Here we characterize ORP5, a tail-anchored ORP protein that localizes to the endoplasmic reticulum. Knocking down ORP5 causes cholesterol accumulation in late endosomes and lysosomes, which is reminiscent of the cholesterol trafficking defect in Niemann Pick C (NPC) fibroblasts. Cholesterol appears to accumulate in the limiting membranes of endosomal compartments in ORP5-depleted cells, whereas depletion of NPC1 or both ORP5 and NPC1 results in luminal accumulation of cholesterol. Moreover, trans-Golgi resident proteins mislocalize to endosomal compartments upon ORP5 depletion, which depends on a functional NPC1. Our results establish the first link between NPC1 and a cytoplasmic sterol carrier, and suggest that ORP5 may cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes.

PMID:
21220512
PMCID:
PMC3019559
DOI:
10.1083/jcb.201004142
[Indexed for MEDLINE]
Free PMC Article
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