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A lysosome‐to‐nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB
Author(s) -
Settembre Carmine,
Zoncu Roberto,
Medina Diego L,
Vetrini Francesco,
Erdin Serkan,
Erdin SerpilUckac,
Huynh Tuong,
Ferron Mathieu,
Karsenty Gerard,
Vellard Michel C,
Facchinetti Valeria,
Sabatini David M,
Ballabio Andrea
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.32
Subject(s) - tfeb , lysosome , mtorc1 , microbiology and biotechnology , biology , autophagy , mechanistic target of rapamycin , pi3k/akt/mtor pathway , basic helix loop helix leucine zipper transcription factors , transcription factor , signal transduction , biochemistry , gene , dna binding protein , enzyme , apoptosis
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.