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mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division

Martina Bonucci1,2,3, Nicolas Kuperwasser1,2,3, Serena Barbe1,2,3

  • 1Institut Necker-Enfants Malades, 14 rue Maria Helena Vieira Da Silva, CS, 61431, Paris, France.

Nature Communications
|June 26, 2020
PubMed

Insights

Hyperactive mTOR signaling causes polycystic kidneys by disrupting cell division. Inhibiting S6K1 restores oriented cell division, preventing cysts and promoting harmonious kidney growth.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • Mammalian target of rapamycin (mTOR) activation is critical in genetic disorders like Tuberous Sclerosis Complex (TSC), leading to polycystic kidneys.
  • Polycystic kidney disease models show increased cell proliferation and cyst formation linked to a loss of oriented cell division (OCD).

Purpose of the Study:

  • To investigate the role of S6 kinase 1 (S6K1) in the loss of OCD and cyst formation in mTOR hyperactivity-driven kidney diseases.
  • To identify S6K1 substrates involved in regulating cell division and kidney development.

Main Methods:

  • Utilized Tsc1-mutant mouse models for studying kidney disease.
  • Employed mass spectrometry-based phosphoproteomics to identify S6K1 substrates.
  • Analyzed cell-cell junctions, protein localization (Afadin, E-cadherin, α-catenin), and centrosome positioning.

Main Results:

  • S6K1 activation was identified as the intrinsic cause of OCD distortion.
  • Loss of S6K1 in Tsc1-mutant mice restored OCD without reducing hyperproliferation, resulting in harmonious kidney overgrowth.
  • Afadin was identified as a direct S6K1 substrate, and its abnormal localization at apical junctions was observed in Tsc1-mutant cells.
  • S6K1 hyperactivity was shown to alter centrosome positioning, impacting OCD and promoting cystogenesis.

Conclusions:

  • S6K1 hyperactivity disrupts OCD by altering Afadin localization and centrosome positioning, contributing to polycystic kidney formation in mTOR hyperactivity conditions.
  • Targeting S6K1 may offer therapeutic strategies for kidney disorders driven by mTOR pathway dysregulation.

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