Lysosomal cholesterol-dependent anabolic regulation

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Project Summary mTORC1 stimulates cell and organ growth mainly by stimulating cellular anabolic processes, including protein, lipid, and nucleotide synthesis, and inhibiting catabolic processes such as autophagy. Aberrant activation of mTORC1 signaling has been linked to many human health problems, including cancer, neurodegenerative diseases, and metabolic disorders such as obesity and diabetes. The activity of mTORC1 is tightly regulated by growth factors and multiple cellular metabolic cues such as amino acids, where amino acids recruit mTORC1 to the lysosome through Rag small GTPases activation, a key process for mTORC1 activation. Although recent studies have revealed the molecular mechanisms by which amino acids induce the lysosomal mTORC1 localization and its activation via Rag GTPases, it has just begun to uncover how cellular lipids such as cholesterol also regulate the activity of mTORC1. A recent study demonstrated that, in addition to amino acids, lysosomal cholesterol also plays a key role in enhancing the activity of Rag GTPases through SLC38A9, the guanine exchange factor for RagA/B. We discovered that BASP1 (Brain abundant signal membrane attached signal protein 1), a known lipid raft cholesterol/PIP2-binding protein, functions as a key stimulator of mTORC1 activity. Mechanistically, BASP1 expresses on the lysosome in a manner dependent on cellular cholesterol and interacts with and inhibits GATOR1, the GTPase activating protein complex for RagA/B, thereby stimulating cellular mTORC1 activity. In addition, ablation of BASP1 largely diminished aberrant mTORC1 activation in cells lacking functional Niemann-Pick Disease, Type C1 (NPC1), a lysosomal cholesterol exporter. Basp1 hypomorphic mice display a reduced developmental growth, reminiscent of mTOR hypomorphic mice or mice treated with the mTORC1 inhibitor, rapamycin. Interestingly, while adult Basp1 hypomorphs show higher insulin sensitivity, they display resistance to diet-induced obesity. We propose that BASP1 plays a crucial role in stimulating cellular mTORC1 activity to induce anabolic processes by sensing lysosomal membrane cholesterol or other lipids and contribute to developmental growth and diet-induced obesity. This proposal will elucidate the molecular mechanisms by which lysosomal lipids enhance BASP1 activity and how BASP1 inhibits GATOR1 activity and investigates the pathophysiological importance of BASP1 in developing metabolic disorders in mice models. Completing this project establishes the role of the NPC1-BASP1-GATOR1-mTORC1 pathway in the regulation of cellular anabolic actions and should yield valuable information to set additional experiments to explore this new branch of lysosomal-oriented mTORC1 regulatory signaling in metabolic disorders and other mTORC1-related human health problems, including neurodegenerative disease, lysosomal storage disorders, and cancer.