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V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis

Eva Maria Gleixner1, Guillaume Canaud2, Tobias Hermle3

  • 1Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.

Cell Reports
|June 24, 2014
PubMed

Insights

The V-ATPase and mTOR signaling pathway regulate epithelial growth by controlling protein uptake. This mechanism ensures proper cell function under normal conditions and prevents excessive uptake during lysosomal stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • The mechanistic target of rapamycin (mTOR) kinase is a key regulator of cell growth, influenced by signals like amino acids and Rheb.
  • The vacuolar-type H+-ATPase (V-ATPase) is implicated in lysosomal amino acid sensing.

Purpose of the Study:

  • To investigate the role of V-ATPase in Rheb-dependent epithelial growth.
  • To elucidate the V-ATPase/mTOR signaling pathway's involvement in apical protein uptake regulation.

Main Methods:

  • Utilized the Drosophila wing as a model epithelium.
  • Investigated Rheb-dependent transcriptional regulation of Megalin.
  • Examined the effects of mTOR inhibition with rapamycin in mouse kidney proximal tubules.

Main Results:

  • V-ATPase is essential for Rheb-dependent epithelial growth in Drosophila.
  • A positive feedback loop involving V-ATPase/mTOR signaling, Rheb, and Megalin controls apical protein uptake.
  • mTOR inhibition reduces Megalin levels and causes proteinuria in mouse kidneys.

Conclusions:

  • The V-ATPase/mTOR pathway, through Megalin, establishes a homeostatic mechanism for epithelial protein uptake.
  • This pathway promotes protein uptake under normal conditions and limits it during lysosomal stress.

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