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TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex

Author

Listed:
  • Nicola Alesi

    (Harvard Medical School)

  • Damir Khabibullin

    (Harvard Medical School)

  • Dean M. Rosenthal

    (Harvard Medical School)

  • Elie W. Akl

    (Harvard Medical School)

  • Pieter M. Cory

    (Harvard Medical School)

  • Michel Alchoueiry

    (Harvard Medical School)

  • Samer Salem

    (Harvard Medical School)

  • Melissa Daou

    (Harvard Medical School)

  • William F. Gibbons

    (Harvard Medical School)

  • Jennifer A. Chen

    (Harvard Medical School)

  • Long Zhang

    (Harvard Medical School)

  • Harilaos Filippakis

    (Harvard Medical School)

  • Laura Graciotti

    (Università Politecnica delle Marche)

  • Caterina Miceli

    (Telethon Institute of Genetics and Medicine)

  • Jlenia Monfregola

    (Telethon Institute of Genetics and Medicine)

  • Claudia Vilardo

    (Telethon Institute of Genetics and Medicine)

  • Manrico Morroni

    (Università Politecnica delle Marche)

  • Chiara Malta

    (Telethon Institute of Genetics and Medicine
    Federico II University)

  • Gennaro Napolitano

    (Telethon Institute of Genetics and Medicine
    Federico II University
    Federico II University)

  • Andrea Ballabio

    (Telethon Institute of Genetics and Medicine
    Federico II University
    Federico II University
    Baylor College of Medicine)

  • Elizabeth P. Henske

    (Harvard Medical School)

Abstract

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin’s benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

Suggested Citation

  • Nicola Alesi & Damir Khabibullin & Dean M. Rosenthal & Elie W. Akl & Pieter M. Cory & Michel Alchoueiry & Samer Salem & Melissa Daou & William F. Gibbons & Jennifer A. Chen & Long Zhang & Harilaos Fil, 2024. "TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44229-4
    DOI: 10.1038/s41467-023-44229-4
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    References listed on IDEAS

    as
    1. Haijuan Yang & Xiaolu Jiang & Buren Li & Hyo J. Yang & Meredith Miller & Angela Yang & Ankita Dhar & Nikola P. Pavletich, 2017. "Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40," Nature, Nature, vol. 552(7685), pages 368-373, December.
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