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TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism

Author

Listed:
  • Nicola Alesi

    (Harvard Medical School)

  • Elie W. Akl

    (Harvard Medical School)

  • Damir Khabibullin

    (Harvard Medical School)

  • Heng-Jia Liu

    (Harvard Medical School)

  • Anna S. Nidhiry

    (Harvard Medical School)

  • Emma R. Garner

    (Harvard Medical School)

  • Harilaos Filippakis

    (Harvard Medical School)

  • Hilaire C. Lam

    (Harvard Medical School)

  • Wei Shi

    (University of Southern California)

  • Srinivas R. Viswanathan

    (Harvard Medical School)

  • Manrico Morroni

    (Università Politecnica delle Marche
    Azienda Ospedaliero-Universitaria)

  • Shawn M. Ferguson

    (Yale University School of Medicine
    Neurodegeneration and Repair, Yale University School of Medicine)

  • Elizabeth P. Henske

    (Harvard Medical School)

Abstract

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). Transcription factor EB (TFEB), a master regulator of lysosome biogenesis, is negatively regulated by mTORC1 through a RAG GTPase-dependent phosphorylation. Here we show that lysosomal biogenesis is increased in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, kidneys from Tsc2+/− mice, and TSC1/2-deficient cells via a TFEB-dependent mechanism. Interestingly, in TSC1/2-deficient cells, TFEB is hypo-phosphorylated at mTORC1-dependent sites, indicating that mTORC1 is unable to phosphorylate TFEB in the absence of the TSC1/2 complex. Importantly, overexpression of folliculin (FLCN), a GTPase activating protein for RAGC, increases TFEB phosphorylation at the mTORC1 sites in TSC2-deficient cells. Overexpression of constitutively active RAGC is sufficient to relocalize TFEB to the cytoplasm. These findings establish the TSC proteins as critical regulators of lysosomal biogenesis via TFEB and RAGC and identify TFEB as a driver of the proliferation of TSC2-deficient cells.

Suggested Citation

  • Nicola Alesi & Elie W. Akl & Damir Khabibullin & Heng-Jia Liu & Anna S. Nidhiry & Emma R. Garner & Harilaos Filippakis & Hilaire C. Lam & Wei Shi & Srinivas R. Viswanathan & Manrico Morroni & Shawn M., 2021. "TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24499-6
    DOI: 10.1038/s41467-021-24499-6
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    References listed on IDEAS

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    1. Alejo Efeyan & William C. Comb & David M. Sabatini, 2015. "Nutrient-sensing mechanisms and pathways," Nature, Nature, vol. 517(7534), pages 302-310, January.
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    1. Yan Tang & David J. Kwiatkowski & Elizabeth P. Henske, 2022. "Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Kaushal Asrani & Juhyung Woo & Adrianna A. Mendes & Ethan Schaffer & Thiago Vidotto & Clarence Rachel Villanueva & Kewen Feng & Lia Oliveira & Sanjana Murali & Hans B. Liu & Daniela C. Salles & Brando, 2022. "An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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