MECHANISMS OF NUTRIENT SIGNAL INTEGRATION AT THE LYSOSOME
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). In response to nutrient abundance, mTORC1 physically translocates from the cytosol to the lysosomal membrane, where its kinase function becomes activated. A central aspect of mTORC1 function that has so far remained poorly understood is its ability to integrate chemically diverse nutrient inputs, and to translate these combined signals into optimal balance of anabolic and catabolic programs.
We recently discovered that mTORC1 specifically senses a cellular lipid, cholesterol, at the lysosome (link). Cholesterol is a key structural component for cellular membranes and precursor for important hormones, but whether and how cholesterol can cross-talk with pathways that regulate cellular metabolism was unknown. We found that cholesterol triggers the recruitment of mTORC1 from the cytoplasm to the surface of lysosomes, concomitant with stimulation 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.
Combining targeted manipulations of the lipid content of selected organelle populations with functional assays for mTORC1 activation, we are elucidating key aspects of this newly identified signaling pathway. In particular, we are investigating i) the identity of cholesterol-binding proteins that activate or inhibit mTORC1 ii) the molecular mechanisms that translate cholesterol levels into Rag GTPase regulation and iii) the physiological and pathogenic roles of the cholesterol-mTORC1 axis. In particular, 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.