| Abstract: | ["In order to grow, cells must tightly coordinate biosynthetic processes with catabolic programs. The master regulator, mechanistic target of rapamycin complex 1 (mTORC1) kinase, integrates signals from nutrients, growth factors and energy to drive cellular growth and homeostasis. Among the nutrient inputs that regulate mTORC1, lipids are currently the least understood. Using biochemical assays in vitro and in intact cells, we recently found that mTORC1 senses the lipid composition of the lysosomal membrane. Cholesterol carried by low-density lipoproteins activates mTORC1 via the heterodimeric Rag GTPases, which anchor mTORC1 to the lysosomal surface. Lipidomics analysis coupled with functional manipulations suggests that a local cholesterol pool modulates protein-protein between the Rag GTPase and the Ragulator complex, leading to mTORC1 recruitment. Together, these data identify lysosomal cholesterol as novel regulatory inputs to mTORC1 and implicate that cholesterol traffic through the endomembrane system may play an important role in mTORC1 signaling and growth regulation."] |
