Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning

TLDR

Late endosome distribution is governed by motor protein interactions, notably the Rab7–RILP–ORP1L complex that recruits the dynactin subunit p150Glued. Low cholesterol induces ORP1L to form ER–LE contacts where VAP binds the Rab7–RILP complex, displacing p150Glued and its motors, thereby driving the vesicles toward microtubule plus ends. The authors demonstrate that cholesterol sensed by ORP1L controls LE positioning: low cholesterol promotes plus‑end movement via ER contacts, while high cholesterol, as in Niemann‑Pick type C, blocks this process and causes LEs to accumulate at microtubule minus ends.

Abstract

Late endosomes (LEs) have characteristic intracellular distributions determined by their interactions with various motor proteins. Motor proteins associated to the dynactin subunit p150Glued bind to LEs via the Rab7 effector Rab7-interacting lysosomal protein (RILP) in association with the oxysterol-binding protein ORP1L. We found that cholesterol levels in LEs are sensed by ORP1L and are lower in peripheral vesicles. Under low cholesterol conditions, ORP1L conformation induces the formation of endoplasmic reticulum (ER)–LE membrane contact sites. At these sites, the ER protein VAP (VAMP [vesicle-associated membrane protein]-associated ER protein) can interact in trans with the Rab7–RILP complex to remove p150Glued and associated motors. LEs then move to the microtubule plus end. Under high cholesterol conditions, as in Niemann-Pick type C disease, this process is prevented, and LEs accumulate at the microtubule minus end as the result of dynein motor activity. These data explain how the ER and cholesterol control the association of LEs with motor proteins and their positioning in cells.