The amino acid transporter SLC38A9 is a key component of a lysosomal membrane complex that signals arginine sufficiency to mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a central controller of growth that responds to the nutritional status of the organism and is deregulated in several diseases, including cancer (1–3). Upon activation, mTORC1 promotes anabolic processes, including protein and lipid synthesis, and inhibits catabolic ones, such as autophagy (4). Environmental cues such as nutrients and growth factors regulate mTORC1, but how it senses and integrates these diverse inputs is unclear. The Rag and Rheb GTPases have essential but distinct roles in mTORC1 pathway activation, with the Rags controlling the subcellular localization of mTORC1 and Rheb stimulating its kinase activity (5). Nutrients, particularly amino acids, activate the Rag GTPases, which then recruit mTORC1 to the lysosomal surface where they are concentrated (6, 7). Rheb also localizes to the lysosomal surface (6, 8–10) and, upon growth factor withdrawal, the tuberous sclerosis complex (TSC) tumor suppressor translocates there and inhibits mTORC1 by promoting GTP hydrolysis by Rheb (10). Thus, the Rag and Rheb inputs converge at the lysosome, forming two halves of a coincidence detector that ensures that mTORC1 activation occurs only when both are active. There are four Rag GTPases in mammals and they form stable, obligate heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB are highly similar and functionally redundant, as are RagC and RagD (1, 6). The function of each Rag within the heterodimer is poorly understood and their regulation is likely complex as many distinct factors play important roles. A lysosome-associated molecular machine containing the multi-subunit Ragulator and vacuolar ATPase (v-ATPase) complexes regulates the Rag GTPases and is necessary for mTORC1 activation by amino acids (11). Ragulator anchors the Rag GTPases to the lysosome and also has nucleotide exchange activity for RagA/B (12, 13), but the molecular function of the v-ATPase in the pathway is unknown. Two GTPase activating protein (GAP) complexes, which are both tumor suppressors, promote GTP hydrolysis by the Rag GTPases, with GATOR1 acting on RagA/B (14) and Folliculin-FNIP2 on RagC/D (15). Lastly, a distinct complex called GATOR2 negatively regulates GATOR1 through an unknown mechanism (14). Despite the identification of many proteins involved in signaling amino acid sufficiency to mTORC1, the actual amino acid sensors remain unknown.