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

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langueAnglais
PagesE3602-E3611
journalProceedings of the National Academy of Sciences of the United States of America
Volume114
Numéro18
Les DOIs
étatPublié - 2017
Modification externeOui

Empreinte digitale

Neutral Amino Acid Transport Systems
Glutamine
Sodium
Growth
Neoplasms
Proteins
Cell Fractionation
Amino Acids
Proton-Motive Force
Asparagine
Autophagy
Gene Silencing
Endocytosis
Lysosomes
Phagocytosis
Cytosol
Proteolysis
Hydrolysis
Transcription Factors
Membranes

mots-clés

    Citer ceci

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    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.",
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    SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells. / Verdon, Quentin; Boonen, Marielle; Ribes, Christopher; Jadot, Michel; GASNIER, Bruno; Sagné, Corinne.

    Dans: Proceedings of the National Academy of Sciences of the United States of America, Vol 114, Numéro 18, 2017, p. E3602-E3611.

    Résultats de recherche: Contribution à un journal/une revueArticle

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    T1 - SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells

    AU - Verdon,Quentin

    AU - Boonen,Marielle

    AU - Ribes,Christopher

    AU - Jadot,Michel

    AU - GASNIER,Bruno

    AU - Sagné,Corinne

    PY - 2017

    Y1 - 2017

    N2 - 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.

    AB - 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.

    KW - Journal Article

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    DO - 10.1073/pnas.1617066114

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    SP - E3602-E3611

    JO - Proceedings of the National Academy of Sciences of the United States of America

    T2 - Proceedings of the National Academy of Sciences of the United States of America

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