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Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning

Nuno Rocha1, Coenraad Kuijl, Rik van der Kant

  • 1Division of Cell Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, Netherlands.

The Journal of Cell Biology
|July 1, 2009
PubMed

Insights

Cholesterol levels regulate late endosome (LE) positioning by controlling motor protein interactions. High cholesterol, seen in Niemann-Pick type C disease, disrupts LE movement, causing cellular accumulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Late endosomes (LEs) exhibit specific intracellular distributions crucial for cellular function.
  • LE positioning is mediated by interactions with motor proteins, influencing their transport along microtubules.
  • The Rab7 effector Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein ORP1L are key in LE-motor protein association.

Purpose of the Study:

  • To investigate the role of cholesterol in regulating late endosome (LE) positioning.
  • To elucidate the molecular mechanisms by which cholesterol levels influence LE-motor protein interactions.
  • To understand how disruptions in cholesterol homeostasis, such as in Niemann-Pick type C disease, affect LE trafficking.

Main Methods:

  • Utilized cell-based assays to examine late endosome (LE) distribution and motor protein association.
  • Investigated the interaction between oxysterol-binding protein ORP1L, Rab7-interacting lysosomal protein (RILP), and motor proteins under varying cholesterol conditions.
  • Analyzed the formation of endoplasmic reticulum (ER)-LE membrane contact sites and the role of VAP (VAMP-associated ER protein) in LE positioning.

Main Results:

  • Cholesterol levels are sensed by ORP1L within late endosomes (LEs), with lower levels found in peripheral LEs.
  • Low cholesterol induces endoplasmic reticulum (ER)-LE membrane contact sites, facilitating the removal of p150(Glued) and promoting LE movement to the microtubule plus end.
  • High cholesterol conditions, mimicking Niemann-Pick type C disease, inhibit this process, leading to LE accumulation at the microtubule minus end via dynein motor activity.

Conclusions:

  • Cholesterol levels dynamically control the association of late endosomes (LEs) with specific motor proteins.
  • Endoplasmic reticulum (ER)-LE membrane contact sites act as regulatory hubs for LE positioning, modulated by cholesterol.
  • Dysregulation of cholesterol homeostasis significantly impacts LE trafficking and cellular organization.

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