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

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

Author information

1
Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
2
INSERM U845, Centre de Recherche "Croissance et Signalisation," Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France.
3
Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
4
Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany.
5
Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany.
6
Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, 24 Boulevard du Montparnasse, 75015 Paris, France. Electronic address: matias.simons@uniklinik-freiburg.de.

Abstract

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.

PMID:
24953654
DOI:
10.1016/j.celrep.2014.05.035
[Indexed for MEDLINE]
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