期刊
CELL REPORTS
卷 8, 期 1, 页码 10-19出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.05.035
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资金
- Emmy-Noether grant by the Deutsche Forschungsgemeinschaft [SI1303/2-1]
- Gerontosys NephAge grant by the German Ministry of Research and Education (BMBF) [0315896]
- NIH [R01GM084947]
- INSERM
- Universite Paris Descartes
- Sorbonne Paris Cite
- ANR
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.
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