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A TFEB nuclear export signal integrates amino acid supply and glucose availability

Author

Listed:
  • Linxin Li

    (University of Oxford)

  • Hans J. Friedrichsen

    (University of Oxford)

  • Sarah Andrews

    (University of Oxford)

  • Sarah Picaud

    (University of Oxford)

  • Laurent Volpon

    (Université de Montréal, Pavillon Marcel-Coutou, Chemin de la Polytechnique)

  • Kaochin Ngeow

    (University of Oxford)

  • Georgina Berridge

    (University of Oxford
    University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Katherine L. B. Borden

    (Université de Montréal, Pavillon Marcel-Coutou, Chemin de la Polytechnique)

  • Panagis Filippakopoulos

    (University of Oxford
    University of Oxford)

  • Colin R. Goding

    (University of Oxford)

Abstract

How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized nuclear export signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a nuclear import-export cycle.

Suggested Citation

  • Linxin Li & Hans J. Friedrichsen & Sarah Andrews & Sarah Picaud & Laurent Volpon & Kaochin Ngeow & Georgina Berridge & Roman Fischer & Katherine L. B. Borden & Panagis Filippakopoulos & Colin R. Godin, 2018. "A TFEB nuclear export signal integrates amino acid supply and glucose availability," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04849-7
    DOI: 10.1038/s41467-018-04849-7
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