SLC38A9 is a component of the lysosomal amino acid-sensing machinery that controls mTORC1

By Manuele Rebsamen, L. Pochini, T. Stasyk, Mariana E. G. de Araujo, M. Galluccio, R. K. Kandasamy, B. Snijder, Astrid Fauster, E. Rudashevskaya, Manuela Bruckner and 10 more. Nature, 2015

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Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H+-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator–RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.

Subfields: Cell Biology, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/49ea1e7758936d6db8c851b2abefe686426cec97

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David M. Sabatini

Citations in the corpus

The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “While Sestrin2 interacts with GATOR2 to inhibit mTORC1 signaling in the absence of leucine, SLC38A9 forms a supercomplexwithRagulator and is necessary for transmitting arginine, but not leucine, sufficiency to mTORC1 (Chantranupong et al., 2014; Jung et al., 2015; Lynch et al., 2000; Rebsamen et al.”
Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, background): “RAG GTPase is activated by the presence of nutrients (e.g. amino acids) through the combined action of the amino acid transporter SLC38A9 (Rebsamen et al., 2015; Wang et al., 2015) and the Ragulator complex as a guanine nucleotide exchange factor (GEF), along with other proteins, which recruit mTORC”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “The lysosomal amino acid transporter SLC38A9 interacts with the Rag-Ragulator-v-ATPase complex and is required for arginine to activate mTORC1, making it a promising candidate to be a lysosomal amino acid sensor (Jung et al., 2015; Rebsamen et al., 2015; Wang et al., 2015).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “The lysosomal amino acid transporter SLC38A9 interacts with the Rag-Ragulator-v-ATPase complex and is required for arginine to activate mTORC1, making it a promising candidate to be a lysosomal amino acid sensor (Jung et al., 2015; Rebsamen et al., 2015; Wang et al., 2015).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Nutrient sensing and TOR signaling in yeast and mammals (2017, neutral): “SLC38A9 binds RAGU-LATOR and RAGs, and knockdown of SLC38A9 impairs arginine-induced activation of mTORC1 (Jung et al , 2015; Rebsamen et al , 2015; Wang et al , 2015; Fig 1).”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “, 2007) and by SLC38A9, leading to inhibition of mTOR (Rebsamen et al., 2015; Wang et al., 2015), which in turn inhibits T cell growth and proliferation.”