RRC ID 32502
Author Gleixner EM, Canaud G, Hermle T, Guida MC, Kretz O, Helmstädter M, Huber TB, Eimer S, Terzi F, Simons M.
Title V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis.
Journal Cell Rep
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.
Volume 8(1)
Pages 10-9
Published 2014-7-10
DOI 10.1016/j.celrep.2014.05.035
PII S2211-1247(14)00429-X
PMID 24953654
MeSH 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*
IF 8.109
Times Cited 29