title: Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth.
abstract: The main organelles of the secretory and endocytic pathways--the endoplasmic reticulum (ER) and endosomes, respectively--are connected through contact sites whose numbers increase as endosomes mature. One function of such sites is to enable dephosphorylation of the cytosolic tails of endosomal signalling receptors by an ER-associated phosphatase, whereas others serve to negatively control the association of endosomes with the minus-end-directed microtubule motor dynein or mediate endosome fission. Cholesterol transfer and Ca(2+) exchange have been proposed as additional functions of such sites. However, the compositions, activities and regulations of ER-endosome contact sites remain incompletely understood. Here we show in human and rat cell lines that protrudin, an ER protein that promotes protrusion and neurite outgrowth, forms contact sites with late endosomes (LEs) via coincident detection of the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P). These contact sites mediate transfer of the microtubule motor kinesin 1 from protrudin to the motor adaptor FYCO1 on LEs. Repeated LE-ER contacts promote microtubule-dependent translocation of LEs to the cell periphery and subsequent synaptotagmin-VII-dependent fusion with the plasma membrane. Such fusion induces outgrowth of protrusions and neurites, which requires the abilities of protrudin and FYCO1 to interact with LEs and kinesin 1. Thus, protrudin-containing ER-LE contact sites are platforms for kinesin-1 loading onto LEs, and kinesin-1-mediated translocation of LEs to the plasma membrane, fuelled by repeated ER contacts, promotes protrusion and neurite outgrowth.
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Camilla
authors: C
authors: Raiborg
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Eva M
authors: EM
authors: Wenzel
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Nina M
authors: NM
authors: Pedersen
authors: Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, N-9037 Tromsø, Norway.
authors: Hallvard
authors: H
authors: Olsvik
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Kay O
authors: KO
authors: Schink
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Sebastian W
authors: SW
authors: Schultz
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Marina
authors: M
authors: Vietri
authors: Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Monteroni 165, 73100 Lecce, Italy.
authors: Veronica
authors: V
authors: Nisi
authors: Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Monteroni 165, 73100 Lecce, Italy.
authors: Cecilia
authors: C
authors: Bucci
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Andreas
authors: A
authors: Brech
authors: Institute of Medical Biology, University of Tromsø - The Arctic University of Norway, N-9037 Tromsø, Norway.
authors: Terje
authors: T
authors: Johansen
authors: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors: Harald
authors: H
authors: Stenmark
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051381:Rats; D050857:Synaptotagmins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D004268:DNA-Binding Proteins; C460141:FYCO1 protein, human; D008869:Microtubule-Associated Proteins; D018129:Phosphatidylinositol Phosphates; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; C513390:ZFYVE27 protein, human; C055525:phosphatidylinositol 3-phosphate; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716466:rab7 GTP-binding proteins, rat; D050857:Synaptotagmins; D016547:Kinesins; D020691:rab GTP-Binding Proteins