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

Abstract

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 responses1-3. 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+ -ATPase 4-8. 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, while 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.

mTOR Signaling in Growth, Metabolism, and Disease

“…Amino acids inside the lysosomal lumen alter the Rag nucleotide state through a mechanism dependent on the lysosomal v-ATPase, which interacts the Ragulator-Rag complex to promote the guanine-nucleotide exchange factor (GEF) activity of Ragulator towards RagA/B (Zoncu et al, 2011;Bar-Peled et al, 2012). 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).…”

Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability

“…In fact, increased activity of mTORC1 in fibroblasts deficient for CD98hc could be attributed to the high content of AA ϩ and glutamine in such cells (Fig. 4A), as arginine and glutamine are also regulators of mTORC1 (32)(33)(34). Alternatively to mTORC1, eukaryotic cells respond to stress (such as oxidative stress or AA deprivation) by phosphorylating the ␣ subunit of the eIF2, which represses global translation coincident with preferential translation of ATF4, a master regulator controlling the transcription of pro-survival target genes (35).…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Glutamine suppresses GCN2 activation and the ISR, which can both otherwise induce autophagy 65,97,127 . Glutamine also indirectly stimulates mTOR, which in turn suppresses autophagy through a complex mechanism 17,[128][129][130][131][132][133][134] (recently reviewed by Dunlop and Tee 135 ). Similarly, ROS can induce autophagy as a stress response 136 but is suppressed by glutamine metabolism through production of glutathione and NADPH 31, 34, 110 .…”