ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signaling in Niemann-Pick type C

Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes via the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signaling are unknown. We show that Oxysterol Binding Protein (OSBP) and its anchors at the endoplasmic reticulum (ER), VAPA/B, deliver cholesterol across ER-lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, mTORC1 recruitment by the Rag GTPases is inhibited due to impaired cholesterol transport to lysosomes. Conversely, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activation in a disease model caused by loss of the lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signaling and restores autophagic function in cellular models of NPC. Thus, ER-lysosome contacts are signaling hubs that enable cholesterol sensing by mTORC1, and targeting their sterol-transfer activity could be beneficial in NPC.