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Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly

Author

Listed:
  • Edoardo Ratto

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • S. Roy Chowdhury

    (German Cancer Research Center (DKFZ))

  • Nora S. Siefert

    (German Cancer Research Center (DKFZ))

  • Martin Schneider

    (German Cancer Research Center (DKFZ))

  • Marten Wittmann

    (German Cancer Research Center (DKFZ))

  • Dominic Helm

    (German Cancer Research Center (DKFZ))

  • Wilhelm Palm

    (German Cancer Research Center (DKFZ))

Abstract

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 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.

Suggested Citation

  • Edoardo Ratto & S. Roy Chowdhury & Nora S. Siefert & Martin Schneider & Marten Wittmann & Dominic Helm & Wilhelm Palm, 2022. "Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32515-6
    DOI: 10.1038/s41467-022-32515-6
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