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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 c...

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Autores principales: Wu, Xiaochun, Zhao, Lingling, Chen, Zhi, Ji, Xin, Qiao, Xianfeng, Jin, Yaping, Liu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900541/
https://www.ncbi.nlm.nih.gov/pubmed/27280402
http://dx.doi.org/10.1371/journal.pone.0157100
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author Wu, Xiaochun
Zhao, Lingling
Chen, Zhi
Ji, Xin
Qiao, Xianfeng
Jin, Yaping
Liu, Wei
author_facet Wu, Xiaochun
Zhao, Lingling
Chen, Zhi
Ji, Xin
Qiao, Xianfeng
Jin, Yaping
Liu, Wei
author_sort Wu, Xiaochun
collection PubMed
description 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.
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spelling pubmed-49005412016-06-24 FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1 Wu, Xiaochun Zhao, Lingling Chen, Zhi Ji, Xin Qiao, Xianfeng Jin, Yaping Liu, Wei PLoS One Research Article 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. Public Library of Science 2016-06-09 /pmc/articles/PMC4900541/ /pubmed/27280402 http://dx.doi.org/10.1371/journal.pone.0157100 Text en © 2016 Wu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wu, Xiaochun
Zhao, Lingling
Chen, Zhi
Ji, Xin
Qiao, Xianfeng
Jin, Yaping
Liu, Wei
FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title_full FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title_fullStr FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title_full_unstemmed FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title_short FLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
title_sort flcn maintains the leucine level in lysosome to stimulate mtorc1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900541/
https://www.ncbi.nlm.nih.gov/pubmed/27280402
http://dx.doi.org/10.1371/journal.pone.0157100
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