Identification of the molecular mechanism by which mTORC1 regulates endolysosomal nutrient acquisition
Final Report Abstract
Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, the nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1), but the underlying mechanism had been unknown. In this DFG-funded research project, we discovered that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing acidification of lysosomes through the proton pump V-ATPase. When mTORC1 is active, peripheral V-ATPase V1 domains reside in the cytosol, where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V1 domains move to membrane-integral V-ATPase Vo domains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes.
Publications
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Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly. Nature Communications, 13(1).
Ratto, Edoardo; Chowdhury, S. Roy; Siefert, Nora S.; Schneider, Martin; Wittmann, Marten; Helm, Dominic & Palm, Wilhelm
