Mechanisms of nutrient sensing by the lysosome

Regulation of mTORC1 signaling by lysosomal cholesterol.  (Left) Working model of mTORC1 activation by cholesterol. Release of cholesterol from LDL in the lysosomal lumen leads to recruitment of mTORC1 to the lysosomal membrane in a SLC38A9- and Rag GTPase-dependent mechanism. (Right) Cholesterol-dependent recruitment of mTOR to LAMP2-positive lysosomes

Regulation of mTORC1 signaling by lysosomal cholesterol. (Left) Working model of mTORC1 activation by cholesterol. Release of cholesterol from LDL in the lysosomal lumen leads to recruitment of mTORC1 to the lysosomal membrane in a SLC38A9- and Rag GTPase-dependent mechanism. (Right) Cholesterol-dependent recruitment of mTOR to LAMP2-positive lysosomes

The molecular mechanisms through which cells sense nutrients remain largely unknown, but their elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of Rapamycin Complex 1 (mTORC1). A central aspect of mTORC1 function that has so far remained poorly understood is its ability to sense lipids. We recently discovered that mTORC1 senses an important lipid, cholesterol, at the lysosome. In particular, addition of cholesterol to cholesterol-depleted cells triggers the recruitment of mTORC1 from the cytoplasm to the surface of lysosomes, concomitant with restoration of the kinase activity of mTORC1. This effect of cholesterol requires the Rag GTPases, which serve as a bridge between mTORC1 and the lysosomal surface. We also identified dedicated lysosomal proteins that convey cholesterol information to the Rag GTPases to trigger mTORC1 activation. 

Using targeted manipulations of the lipid content of selected organelle populations combined with reconstitution-based assays of mTORC1 activation, we are elucidating key aspects of this newly identified signaling pathway. In particular, we are investigating i) the cellular location of the cholesterol pools that regulate mTORC1 ii) the role of inter-organelle contacts in relaying cholesterol for mTORC1 activation and iii) the molecular mechanisms through which cholesterol induces mTORC1 recruitment to the lysosomal surface. Moreover, our work is illuminating how aberrant cholesterol sensing by mTORC1 could disrupt cellular quality control and drive the metabolic and neurodegenerative disease, Niemann-Pick type C.