A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB
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Author(s)
Settembre, Carmine
Zoncu, Roberto
Medina, Diego L.
Vetrini, Francesco
Erdin, Serkan
Erdin, SerpilUckac
Huynh, Tuong
Ferron, Mathieu
Karsenty, Gerard
Vellard, Michel C.
Date Issued
March 2012
Journal
EMBO Journal
Publisher
EMBRO Press
Citation
Settembre, Carmine, Roberto Zoncu, Diego L Medina, Francesco Vetrini, Serkan Erdin, SerpilUckac Erdin, Tuong Huynh, et al. “A Lysosome-to-Nucleus Signalling Mechanism Senses and Regulates the Lysosome via mTOR and TFEB.” The EMBO Journal 31, no. 5 (February 17, 2012): 1095–1108.
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Final published version
Abstract
The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB−/− cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation‐ and stress‐induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome‐to‐nucleus signalling mechanism that involves TFEB and mTOR.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/emboj.2012.32
