Abstract
SLC38A9 acts as a lysosomal arginine sensor to activate mTORC1 signaling and support tumor growth.
Major finding: SLC38A9 acts as a lysosomal arginine sensor to activate mTORC1 signaling and support tumor growth.
Mechanism: SLC38A9 promotes arginine-dependent transport of leucine out of the lysosome to activate mTORC1.
Impact: SLC38A9 loss may suppress growth of tumors that rely on macropinocytosed protein as a nutrient source.
The mTORC1 protein kinase regulates anabolic and catabolic processes, responding to environmental cues to control cell growth, and is often dysregulated in cancer. The lysosomal membrane protein SLC38A9 is required for arginine-mediated mTORC1 activation, but the underlying molecular mechanism is unclear. Wyant, Abu-Remaileh, and colleagues hypothesized that SLC38A9 functions as a lysosomal arginine sensor for the mTORC1 pathway. Consistent with this hypothesis, an SLC38A9 mutant incapable of binding arginine was not able to promote signaling arginine sufficiency to activate mTORC1. Rag GTPases recruit mTORC1 to the lysosome in response to amino acids, and arginine in the lysosome promoted the interaction between SLC38A9 and the Rag GTPase-Ragulator complex, further supporting a role for SLC38A9 as an arginine sensor. Mechanistically, SLC38A9 served as a high-affinity leucine transporter, with loss of SLC38A9 resulting in lysosomal amino acid accumulation, and, thereby, arginine regulated the lysosomal concentrations of amino acids by binding to SLC38A9. Specifically, SLC38A9 transported leucine produced via autophagy into the cytosol where it activated mTORC1. In pancreatic cancer cells, which obtain extracellular proteins via macropinocytosis as a nutrient source, loss of SLC38A9 prevented arginine-induced mTORC1 activation and blocked albumin from reactivating mTORC1 signaling in leucine-starved cells. Thus, SLC38A9 depletion suppressed pancreatic cancer cell growth in vitro when albumin was the available leucine source. Further, SLC38A9 loss suppressed tumor formation in vivo in a KRASG12D/+TP53−/− pancreatic cancer orthotopic allograft model. Taken together, these results demonstrate that SLC38A9 functions as an arginine sensor in cancer cells, coupling mTORC1 activation with the release of amino acids from the lysosome for use as a nutrient source to promote cell growth.
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