Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth

Nature. 2015 Apr 9;520(7546):234-8. doi: 10.1038/nature14359.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • Cell Line
  • Cell Membrane / metabolism
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endosomes / metabolism*
  • HeLa Cells
  • Humans
  • Kinesin / metabolism
  • Microtubule-Associated Proteins
  • Microtubules / metabolism
  • Neurites / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Rats
  • Synaptotagmins / metabolism
  • Transcription Factors / metabolism
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • FYCO1 protein, human
  • Microtubule-Associated Proteins
  • Phosphatidylinositol Phosphates
  • Transcription Factors
  • Vesicular Transport Proteins
  • ZFYVE27 protein, human
  • phosphatidylinositol 3-phosphate
  • Synaptotagmins
  • rab7 protein
  • Kinesin
  • rab GTP-Binding Proteins