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Media type:
E-Article
Title:
Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly
Contributor:
Ratto, Edoardo;
Chowdhury, S. Roy;
Siefert, Nora S.;
Schneider, Martin;
Wittmann, Marten;
Helm, Dominic;
Palm, Wilhelm
imprint:
Springer Science and Business Media LLC, 2022
Published in:Nature Communications
Language:
English
DOI:
10.1038/s41467-022-32515-6
ISSN:
2041-1723
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V<jats:sub>1</jats:sub> 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 V<jats:sub>1</jats:sub> domains move to membrane-integral V-ATPase V<jats:sub>o</jats:sub> 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.</jats:p>