Cells rely on metabolic control; the mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, particularly amino acids. Lysosomes maintain amino acid homeostasis through recycling. SLC38A9, a lysosomal amino acid transporter, functions as a critical sensor in the mTORC1 pathway. Here, we investigate how pH regulates SLC38A9 activity. We show that arginine uptake is pH-dependent, with His544 residue serving as the pH sensor. Mutating His544 abolishes pH dependence without impairing overall transport, indicating His544 influences transport through protonation/deprotonation, instead of involving in the substrate binding. We propose a working model for pH-induced activation, through comparing two determined SLC38A9 structures at different pH. These findings reveal how local ionic shifts regulate lysosomal transporters and fine-tune SLC38A9 function to control mTORC1 signaling.
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Xuelang Mu
Ampon Sae Her
Tamir Gonen
FEBS Letters
Howard Hughes Medical Institute
University of California, Los Angeles
Molecular Sciences Institute
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Mu et al. (Sun,) studied this question.
www.synapsesocial.com/papers/69fa97ce04f884e66b5319e9 — DOI: https://doi.org/10.1002/1873-3468.70352
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