Open AccessFLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
Author(s) -
Xiaochun Wu,
Lingling Zhao,
Zhi Chen,
Xin Ji,
Xianfeng Qiao,
Yaping Jin,
Wei Liu
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0157100
Subject(s) - folliculin , mtorc1 , lysosome , leucine , microbiology and biotechnology , amino acid transporter , amino acid , biology , biochemistry , signal transduction , chemistry , pi3k/akt/mtor pathway , transporter , gene , enzyme
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.