SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells

Quentin Verdon, Marielle Boonen, Christopher Ribes, Michel Jadot, Bruno GASNIER, Corinne Sagné

Research output: Contribution to journalArticle

Abstract

Lysosomes degrade cellular components sequestered by autophagy or extracellular material internalized by endocytosis and phagocytosis. The macromolecule building blocks released by lysosomal hydrolysis are then exported to the cytosol by lysosomal transporters, which remain undercharacterized. In this study, we designed an in situ assay of lysosomal amino acid export based on the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis that detects lysosomal storage. This assay was used to screen candidate lysosomal transporters, leading to the identification of sodium-coupled neutral amino acid transporter 7 (SNAT7), encoded by the SLC38A7 gene, as a lysosomal transporter highly selective for glutamine and asparagine. Cell fractionation confirmed the lysosomal localization of SNAT7, and flux measurements confirmed its substrate selectivity and showed a strong activation by the lysosomal pH gradient. Interestingly, gene silencing or editing experiments revealed that SNAT7 is the primary permeation pathway for glutamine across the lysosomal membrane and it is required for growth of cancer cells in a low free-glutamine environment, when macropinocytosis and lysosomal degradation of extracellular proteins are used as an alternative source of amino acids. SNAT7 may, thus, represent a novel target for glutamine-related anticancer therapies.

Original languageEnglish
Pages (from-to)E3602-E3611
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number18
DOIs
Publication statusPublished - 2 May 2017
Externally publishedYes

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Keywords

  • Journal Article
  • Lysosome
  • Cell nutrition
  • Transporter
  • Cancer
  • Glutamine
  • Glutamine/genetics
  • Humans
  • Tumor Microenvironment
  • Neoplasms/genetics
  • Amino Acid Transport Systems, Neutral/genetics
  • Intracellular Membranes/metabolism
  • Neoplasm Proteins/genetics
  • Lysosomes/genetics
  • HeLa Cells

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