A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

Authors

  • Carmine Settembre,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    3. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
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    • These authors contributed equally to this work
  • Roberto Zoncu,

    1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, USA
    2. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
    3. David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
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    • These authors contributed equally to this work
  • Diego L Medina,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
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  • Francesco Vetrini,

    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    3. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
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  • Serkan Erdin,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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  • SerpilUckac Erdin,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    2. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
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  • Tuong Huynh,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    2. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
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  • Mathieu Ferron,

    1. Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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  • Gerard Karsenty,

    1. Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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  • Michel C Vellard,

    1. BioMarin Pharmaceutical Inc, Novato, CA, USA
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  • Valeria Facchinetti,

    1. Department of Immunology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • David M Sabatini,

    1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, USA
    2. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
    3. David H Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    4. Seven Cambridge Center, Broad Institute, Cambridge, MA, USA
    5. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
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  • Andrea Ballabio

    Corresponding author
    1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    3. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
    4. Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy
    • Corresponding author. Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, Naples 80131, Italy. Tel.: +39 081 6132207; Fax: +39 081 579 0919; E-mail: ballabio@tigem.it

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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.

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