Journal
NATURE
Volume 520, Issue 7546, Pages 234-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14359
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Funding
- Associazione Italiana per la Ricerca sul Cancro [14709]
- Telethon-Italy [GGP09145]
- MIUR (PRIN)
- Norwegian Research Council [196898]
- Norwegian Cancer Society [71043-PR-2006-0320]
- European Research Council
- Research Council of Norway through its Centres of Excellence funding scheme [179571]
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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(1-3). One function of such sites is to enable dephosphorylation of the cytosolic tails of endosomal signalling receptors by an ER-associated phosphatase(4), whereas others serve to negatively control the association of endosomes with the minus-end-directed microtubule motor dynein(5) or mediate endosome fission(6). Cholesterol transfer and Ca2+ exchange have been proposed as additional functions of such sites(2,3). 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(7), 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 fromprotrudin 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.
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