The lysosome is a eukaryotic organelle that coordinates degradative pathways with nutrient sensing and signalling. It therefore dictates cell growth and survival depending on nutrient availability. Dissecting the molecular machinery that enables these functions is of key importance to cell biology. The mTORC1 complex controls cell proliferation and metabolism by nutrient sensing at lysosomes and late endosomes (LyLEs). Recent work from the host revealed that during nutrient starvation, mTORC1 is repressed by the lipid PI(3,4)P2 at LyLEs which is produced by the class II phosphoinositide 3-kinase PI3KC2β. PI3KC2β is recruited to LyLEs via an interaction of its N-terminus with the Raptor subunit of mTORC1. The precise mechanisms of PI3KC2β regulation at LyLEs are unknown. Using a diverse suite of structural and biochemical methods, I propose to define how complex formation of PI3KC2β with mTORC1 and other LyLE associated proteins governs nutrient signaling and protein turnover at LyLEs. The proposed research may pave the way to combat diseases ranging from diabetes to cancer.
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