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

The mTORC1 protein kinase complex integrates nutrient and growth stimuli to modulate signalling pathways that regulate cellular metabolism and physiology, but the molecular nature of the amino acid sensing mechanism at the lysosome is unknown; here, an orphan member of the human solute carrier group of proteins, SLC38A9, is shown to be an integral component of the lysosomal machinery that can directly sense amino acids and activate mTORC1. The mTORC1 protein kinase complex integrates nutrients and growth stimuli to modulate signalling pathways that regulate cellular metabolism and physiology. Although amino acids are essential for mTORC1 activity, the molecular nature of the amino-acid-sensing mechanism at the lysosome is unknown. Here, Giulio Superti-Furga and colleagues discover a member of the human solute carrier group of proteins, SLC38A9, to be an integral component of the lysosomal machinery that can directly sense amino acids and activate mTORC1. 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 responses1,2,3. 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+-ATPase4,5,6,7,8. 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.