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

• 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

SummarymTOR 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.

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