Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning.
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.
Rocha
Nuno
N
Division of Cell Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, Netherlands.
Kuijl
Coenraad
C
van der Kant
Rik
R
Janssen
Lennert
L
Houben
Diane
D
Janssen
Hans
H
Zwart
Wilbert
W
Neefjes
Jacques
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000736:Androstenes / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D000072159:Dynactin Complex; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008148:Lovastatin / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D000098825:Oxysterol Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D000736:Androstenes; D000924:Anticholesteremic Agents; D002352:Carrier Proteins; C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; C423317:RILP protein, human; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; C114051:VAPA protein, human; D033921:Vesicular Transport Proteins; D000098825:Oxysterol Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D008148:Lovastatin; D020691:rab GTP-Binding Proteins