title: Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L.
abstract: Late endosomes and lysosomes are dynamic organelles that constantly move and fuse to acquire cargo from early endosomes, phagosomes and autophagosome. Defects in lysosomal dynamics cause severe neurodegenerative and developmental diseases, such as Niemann-Pick type C disease and ARC syndrome, yet little is known about the regulation of late endosomal fusion in a mammalian system. Mammalian endosomes destined for fusion need to be transported over very long distances before they tether to initiate contact. Here, we describe that lysosomal tethering and transport are combined processes co-regulated by one multi-protein complex: RAB7-RILP-ORP1L. We show that RILP directly and concomitantly binds the tethering HOPS complex and the p150(Glued) subunit of the dynein motor. ORP1L then functions as a cholesterol-sensing switch controlling RILP-HOPS-p150(Glued) interactions. We show that RILP and ORP1L control Ebola virus infection, a process dependent on late endosomal fusion. By combining recruitment and regulation of both the dynein motor and HOPS complex into a single multiprotein complex, the RAB7-RILP-ORP1L complex efficiently couples and regulates the timing of microtubule minus-end transport and fusion, two major events in endosomal biology.
authors.affiliation: Division of Cell Biology II, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: van der Kant
authors.forename: Alexander
authors.initials: A
authors.lastname: Fish
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.forename: Sabine
authors.initials: S
authors.lastname: Krom
authors.forename: Nataschja
authors.initials: N
authors.lastname: Ho
authors.forename: Thijn
authors.initials: T
authors.lastname: Brummelkamp
authors.forename: Jan
authors.initials: J
authors.lastname: Carette
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C423317:RILP protein, human; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D002784:Cholesterol; D004398:Dyneins; D020691:rab GTP-Binding Proteins
keywords: Dynein; Ebola virus; Endosomal fusion; HOPS complex; ORP1L; RAB7; RILP