Investigation of a novel protein complex that couples regulation of lysosomal function to intracellular nutrient availability

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 DESCRIPTION (provided by applicant): Cells respond to changes in nutrient availability by adjusting growth and biosynthetic activities. Nutrient rich conditions promote anabolic processes such as protein and lipid synthesis, while nutrient poor conditions promote catabolic processes such as the degradation of macromolecules within lysosomes. Lysosomes furthermore serve as a signaling platform that helps cells to coordinate their responses to changes in nutrient availability. For example, the activation of mTORC1, a central coordinator of cell growth and metabolism, is regulated by its nutrient-regulated recruitment to the surface of lysosomes where it can subsequently be activated by growth factor signals. Given the major role for mTORC1 as a regulator of cell growth in both health and disease, there is currently intense interest in the identification and functional characterization of the lysosomal proteins that directly sense and/or respond to changes in nutrient availability. Our lab recently identified a critical lysosome-localized role for folliculin (FLCN), the Birt-Hogg-Dubé syndrome tumor suppressor, in the activation of mTORC1 by intracellular amino acids. The goal of this proposal is to define the role of a novel protein complex made up of proteins that are predicted to be structurally homologous to FLCN in lysosome-based nutrient sensing and signaling pathways. I will investigate the function of these proteins by using biochemical, genetic and cell-based assays to test my hypothesis that these proteins contribute to the ability of lysosomes to sense and respond to ongoing changes in nutrient availability. The proposed research is broadly relevant to the NIH mission as dysregulation of nutrient-imposed constraints on cell growth are frequently observed in cancer. This is best highlighted by reports that mTORC1 signaling is hyperactivated in more than half of all tumors. Aberrant mTORC1 signaling has also been linked to neurological disease. These examples illustrate how defining the molecular mechanisms that allow lysosomes to respond to intracellular nutrient availability is of importance to human health.