title: A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.
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.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.forename: SerpilUckac
authors.initials: S
authors.lastname: Erdin
authors.forename: Tuong
authors.initials: T
authors.lastname: Huynh
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Michel C
authors.initials: MC
authors.lastname: Vellard
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D046912:Multiprotein Complexes; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051907:Lysosomal Membrane Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C064972:TFEB protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases