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

Kaushal Asrani1, Juhyung Woo2, Adrianna A Mendes2

  • 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kasrani1@jhmi.edu.

Nature Communications
|November 10, 2022
PubMed

Insights

Loss of TSC2 in renal cells impairs a feedback loop controlling mTORC1 signaling, leading to MiT/TFE transcription factor activation and potential oncogenesis. This study reveals a novel autoregulation mechanism for mTORC1 activity.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of nutrient sensing
  • Cancer biology and genetics

Background:

  • The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, integrating signals from nutrients and growth factors.
  • MiT/TFE transcription factors are regulated by mTORC1, influencing cellular responses to nutrient availability.
  • Autoregulation of mTORC1 activity is crucial but not fully understood.

Purpose of the Study:

  • To investigate the autoregulation of mTORC1 activity, particularly how it is constrained.
  • To elucidate the role of the FLCN:FNIP2 complex in regulating RagC GTPase activity and mTORC1 signaling.
  • To understand the implications of impaired feedback loops in renal cells with TSC2 loss for oncogenesis.

Main Methods:

  • Analysis of lysosomal recruitment and phosphorylation status of MiT/TFE factors in renal cells.
  • Investigation of the FLCN:FNIP2 complex localization and function under nutrient-rich and starvation conditions.
  • Utilizing FLCN mutants and forced localization to rescue TFEB phosphorylation in TSC2-null cells.

Main Results:

  • Starvation-induced lysosomal localization of FLCN:FNIP2 is impaired in TSC2-null renal cells in an mTORC1-sensitive manner.
  • TSC2 loss leads to TFEB hypophosphorylation and activation upon feeding, indicating dysregulated mTORC1 signaling.
  • Restoration of TFEB phosphorylation is achieved by destabilizing the lysosomal folliculin complex (LFC) or forcing FLCN:FNIP2 localization.

Conclusions:

  • A negative feedback loop involving FLCN:FNIP2 constrains RagC activity in response to amino acids in renal cells with constitutive mTORC1 signaling.
  • Hyperactivation of MiT/TFE factors due to impaired feedback may contribute to oncogenesis in the context of TSC2 loss.
  • This study uncovers a novel mechanism of mTORC1 autoregulation with implications for kidney cancer development.

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