Abstract
The intracellular amino acid pool within lysosome is a signal that stimulates the nutrient-sensing mTORC1 signalling pathway. The signal transduction cascade has garnered much attention, but little is known about the sequestration of the signalling molecules within the lysosome. Using human HEK293 cells as a model, we found that suppression of the BHD syndrome gene FLCN reduced the leucine level in lysosome, which correlated with decreased mTORC1 activity. Both consequences could be reversed by supplementation with high levels of leucine, but not other tested amino acids. Conversely, overexpressed FLCN could sequester lysosomal leucine and stimulate mTORC1 in an amino acid limitation environment. These results identify a novel function of FLCN: it controls mTORC1 by modulating the leucine signal in lysosome. Furthermore, we provided evidence that FLCN exerted this role by inhibiting the accumulation of the amino acid transporter PAT1 on the lysosome surface, thereby maintaining the signal level within the organelle.
Highlights
The ancient mechanistic target of rapamycin signalling pathway is critical for cells to adjust their metabolism to the available nutrients
Rheb itself is inactivated by the tuberous sclerosis complex (TSC), which is excluded from lysosomes in the presence of growth factors [9]
Using human embryonic kidney 293 (HEK293) cells as a model, we found that lysosomal leucine was reduced upon FLCN suppression, causing decreased mTORC1 activity
Summary
The ancient mechanistic target of rapamycin (mTOR) signalling pathway is critical for cells to adjust their metabolism to the available nutrients. The central factor in this process is mTOR, a protein kinase whose targets include key regulators of protein synthesis. The amino acid pool within lysosome serves as a signal to sequentially recruit Ragulator and the heterodimeric Rag GTPase complex with the help of lysosome-associated vacuolar-type H+ ATPase (v-ATPase). Rheb itself is inactivated by the tuberous sclerosis complex (TSC), which is excluded from lysosomes in the presence of growth factors [9]. Lysosome plays at least two roles in mTORC1 signalling. It provides a physical space where activation takes place; second, its content of amino acids activates the signalling. Most studies have focused on the cascade that transfers the luminal signal to mTORC1, but the sequestration of upstream cues within the lysosomal lumen remains poorly understood
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