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An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss

Author

Listed:
  • Kaushal Asrani

    (Johns Hopkins University School of Medicine)

  • Juhyung Woo

    (Johns Hopkins University School of Medicine)

  • Adrianna A. Mendes

    (Johns Hopkins University School of Medicine)

  • Ethan Schaffer

    (Johns Hopkins University School of Medicine)

  • Thiago Vidotto

    (Johns Hopkins University School of Medicine)

  • Clarence Rachel Villanueva

    (Johns Hopkins University School of Medicine)

  • Kewen Feng

    (Johns Hopkins University School of Medicine)

  • Lia Oliveira

    (Johns Hopkins University School of Medicine)

  • Sanjana Murali

    (Johns Hopkins University School of Medicine)

  • Hans B. Liu

    (Johns Hopkins University School of Medicine)

  • Daniela C. Salles

    (Johns Hopkins University School of Medicine)

  • Brandon Lam

    (Johns Hopkins University School of Medicine)

  • Pedram Argani

    (Johns Hopkins University School of Medicine)

  • Tamara L. Lotan

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34617-7
    DOI: 10.1038/s41467-022-34617-7
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