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

By Shuyu Wang, Z. Tsun, Rachel L. Wolfson, K. Shen, Gregory A. Wyant, Molly E. Plovanich, Elizabeth D. Yuan, Tony Jones, Lynne Chantranupong, William C. Comb and 8 more. Science, 2015

763 citations recorded by the source corpus.

Sensing amino acids at the lysosome The mTORC1 protein kinase is a complex of proteins that functions to regulate growth and metabolism. Activity of mTORC1 is sensitive to the abundance of amino acids, but how the sensing of amino acids is coupled to the control of mTORC1 has been unclear. Wang et al. searched for predicted membrane proteins that interacted with regulators of mTORC1. They identified a protein currently known only as SLC38A9. Interaction of SLC38A9 with mTORC1 regulators was sensitive to the presence of amino acids. SLC38A9 has sequence similarity to amino acid transporters. Effects of modulation of SLC38A9 in cultured human cells indicate that it may be the sensor that connects the abundance of arginine and leucine to mTORC1 activity. Science, this issue p. 188 A possible sensor for detecting and signaling amino acid abundance is identified. [Also see Perspective by Abraham] The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase–dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid–sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/5f53968d110eb8413882b9c730fa7ac846b0e5e7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

In Molecular Biology

In Physiology

Citations in the corpus

Sestrin2 is a leucine sensor for the mTORC1 pathway (2015, background): “While SLC38A9 is a strong candidate for sensing arginine at lysosomes (23), the long-sought sensor of leucine was unknown.”
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).”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “Lack of L-arginine in T cells can be sensed by GCN2, leading to an amino acid starvation response (Rodriguez et al., 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.”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
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).”
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).”
AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. (2020, background): “The lysosomal amino acid 568 transporter SLC38A9 (Jung et al., 2015; Rebsamen et al., 2015; Wang et al., 2015b; Wyant et al., 569 2017) acts as a GEF for RAGA (Shen and Sabatini, 2018).”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “Despite these advances, in human cells lacking SLC38A9 arginine starvation still inhibits mTORC1 (Wang et al., 2015), suggesting that our understanding of how arginine is sensed is incomplete.”