FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1.
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.
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Xiaochun
X
Wu
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Lingling
L
Zhao
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Zhi
Z
Chen
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Xin
X
Ji
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Xianfeng
X
Qiao
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Yaping
Y
Jin
Key Laboratory of Animal Biotechnology, the Ministry of Agriculture, College of Veterinary Medicine, Northwest Agriculture & Forest University, Yangling, Shaanxi, China.
Wei
W
Liu
D000818:Animals; D004331:Drosophila melanogaster / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C476078:FLCN protein, human; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine