V-ATPase/mTOR Signaling Regulates Megalin-Mediated Apical Endocytosis

• Published in: Cell reports (Cambridge) Vol. 8; no. 1; pp. 10 - 19
• Main Authors: Gleixner, Eva Maria, Canaud, Guillaume, Hermle, Tobias, Guida, Maria Clara, Kretz, Oliver, Helmstädter, Martin, Huber, Tobias B., Eimer, Stefan, Terzi, Fabiola, Simons, Matias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2014; Elsevier
• Subjects: 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
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.05.035

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. [Display omitted] •The V-ATPase is required for mTOR-dependent tissue growth in Drosophila•V-ATPase/mTOR signaling controls apical endocytosis•Megalin activity and apical surface area is regulated by V-ATPase/mTOR signaling•Long-term mTOR inhibition causes Megalin downregulation and proteinuria in the kidney Epithelial growth requires the endocytic uptake of proteins, which are broken down into amino acids. Amino acids recruit the growth-regulating mTORC1 complex to the lysosomal surface, thereby causing its activation. Gleixner et al. now find that in epithelial cells apical protein uptake is controlled by the lysosomal V-ATPase/mTORC1 complex in a feedforward manner. The multiligand receptor Megalin, which internalizes proteins on the apical surface, is crucial for this regulatory pathway.