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Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150^Glued and late endosome positioning

¹ Division of Cell Biology and ² Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, Netherlands

Correspondence to Wilbert Zwart: w.zwart{at}nki.nl; or Jacques Neefjes: j.neefjes{at}nki.nl

Late endosomes (LEs) have characteristic intracellular distributions determined by their interactions with various motor proteins. Motor proteins associated to the dynactin subunit p150^Glued bind to LEs via the Rab7 effector Rab7-interacting lysosomal protein (RILP) in association with the oxysterol-binding protein ORP1L. We found that cholesterol levels in LEs are sensed by ORP1L and are lower in peripheral vesicles. Under low cholesterol conditions, ORP1L conformation induces the formation of endoplasmic reticulum (ER)–LE membrane contact sites. At these sites, the ER protein VAP (VAMP [vesicle-associated membrane protein]-associated ER protein) can interact in trans with the Rab7–RILP complex to remove p150^Glued and associated motors. LEs then move to the microtubule plus end. Under high cholesterol conditions, as in Niemann-Pick type C disease, this process is prevented, and LEs accumulate at the microtubule minus end as the result of dynein motor activity. These data explain how the ER and cholesterol control the association of LEs with motor proteins and their positioning in cells.

Abbreviations used in this paper: BP, band pass; CLSM, confocal laser-scanning microscopy; DIC, dynein intermediate chain; FLIM, fluorescence lifetime imaging microscopy; FRET, fluorescence resonance energy transfer; IMDM, Iscove's modified Dulbecco's medium; LE, late endosome; LUT, look up table; MBP, maltose-binding protein; MCS, membrane contact site; mRFP, monomeric RFP; MTOC, microtubule-organizing center; ORD, OSBP-related domain; OSBP, oxysterol-binding protein; PH, pleckstrin homology; qPCR, quantitative PCR; RILP, Rab7-interacting lysosomal protein; VAP, VAMP-associated ER protein.

© 2009 Rocha et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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