title: V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis.
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.
authors: Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors: Eva Maria
authors: EM
authors: Gleixner
authors: INSERM U845, Centre de Recherche "Croissance et Signalisation," Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors: Guillaume
authors: G
authors: Canaud
authors: Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors: Tobias
authors: T
authors: Hermle
authors: Center for Systems Biology (ZBSA), University of Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors: Maria Clara
authors: MC
authors: Guida
authors: 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.
authors: Oliver
authors: O
authors: Kretz
authors: Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors: Martin
authors: M
authors: Helmstädter
authors: Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany.
authors: Tobias B
authors: TB
authors: Huber
authors: 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.
authors: Stefan
authors: S
authors: Eimer
authors: INSERM U845, Centre de Recherche "Croissance et Signalisation," Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors: Fabiola
authors: F
authors: Terzi
authors: 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.
authors: Matias
authors: M
authors: Simons
mesh_terms: D000818:Animals; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D004848:Epithelium / Q000254:growth & development / Q000378:metabolism; D025461:Feedback, Physiological; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490212:Rheb protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases; D020559:Monomeric GTP-Binding Proteins