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

Cell Rep. 2014 Jul 10;8(1):10-9. doi: 10.1016/j.celrep.2014.05.035. Epub 2014 Jun 19.


mTOR kinase is a master growth regulator that can be stimulated by multiple signals, including amino acids and the lysosomal small GTPase Rheb. Recent studies have proposed an important role for the V-ATPase in the sensing of amino acids in the lysosomal lumen. Using the Drosophila wing as a model epithelium, we show here that the V-ATPase is required for Rheb-dependent epithelial growth. We further uncover a positive feedback loop for the control of apical protein uptake that depends on V-ATPase/mTOR signaling. This feedback loop includes Rheb-dependent transcriptional regulation of the multiligand receptor Megalin, which itself is required for Rheb-induced endocytosis. In addition, we provide evidence that long-term mTOR inhibition with rapamycin in mice causes reduction of Megalin levels and proteinuria in the proximal tubular epithelium of the kidney. Thus, our findings unravel a homeostatic mechanism that allows epithelial cells to promote protein uptake under normal conditions and to prevent uptake in lysosomal stress conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Endocytosis*
  • Epithelium / growth & development
  • Epithelium / metabolism
  • Feedback, Physiological
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Proteinuria / metabolism
  • Ras Homolog Enriched in Brain Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism*


  • Drosophila Proteins
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Neuropeptides
  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, Drosophila
  • TOR Serine-Threonine Kinases
  • Vacuolar Proton-Translocating ATPases
  • Monomeric GTP-Binding Proteins