Cited by 266PI3K/AKT/mTOR signaling in cancerAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

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Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9

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Jung, Jennifer, Genau, Heide Marika, Behrends, Christian·2015·Molecular and Cellular Biology

DOI 10.1128/mcb.00125-15PMC PMC4475919

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Abstract

The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Depletion of SLC38A9 inhibits mTORC1 activity in the presence of amino acids and in response to amino acid replenishment following starvation. Conversely, SLC38A9 overexpression causes RHEB (Ras homolog enriched in brain) GTPase-dependent hyperactivation of mTORC1 and partly sustains mTORC1 activity upon amino acid deprivation. Intriguingly, during amino acid starvation mTOR is retained at the lysosome upon SLC38A9 depletion but fails to be activated. Together, the findings of our study reveal SLC38A9 as a Rag-Ragulator complex member transducing amino acid availability to mTORC1 activity.

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Authors: Jung, J., Genau, H. M., & Behrends, C.
Affiliations: Goethe University Frankfurt (DE)
Corresponding author: Behrends, Christian
ORCID: Jung, Jennifer
Behrends, Christian
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2015-07-01
Volume: 35
Issue: 14
Pages: 2479-2494
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.00125-15
PMC: PMC4475919
OpenAlex: W2257572427
Cited by: 266
References: 55
Citations by year: 2026: 9 · 2025: 11 · 2024: 16 · 2023: 23 · 2022: 23 · 2021: 37 · 2020: 20 · 2019: 28 · 2018: 29 · 2017: 33 · 2016: 30 · 2015: 6
FWCI: 14.19
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft (BE 4685/1‐1)
FP7 Ideas: European Research Council (282333)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: SLC38A9, mTORC1, Rag GTPases, amino acid signaling, lysosomes, Rheb, amino acid starvation, transmembrane proteins, translational regulation
MeSH terms: Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Fluorescent Antibody Technique, Humans, Lysosomes, Neuropeptides, Protein Binding, Immunoblotting, GTP Phosphohydrolases, Monomeric GTP-Binding Proteins, Amino Acid Transport Systems, RNA Interference, Multiprotein Complexes, HEK293 Cells, TOR Serine-Threonine Kinases, Protein Interaction Maps

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Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9

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