Project 7 - Role of ClC-5 and other vesicular CLC transporters in renal endocytosis and tubular transport

Project Summary

ClC-5 is an electrogenic Cl-/H+-exchanger that is mainly expressed in apical endosomes of proximal tubular cells. Mutations in ClC-5 underlie Dent’s disease, an X-linked disorder that is characterized by low molecular weight proteinuria, hypercalciuria and kidney stones. When we disrupted ClC-5 in mice, we observed a cell-intrinsic defect in endocytosis that we attributed to an impaired luminal acidification of endosomes. We found also that the abundance and subcellular distribution of megalin, a multi-ligand apical receptor that is important for endocytosis of many substances, was changed as well. This finding, which should further inhibit receptor-mediated endocytosis, was attributed to a defective recycling of meglain back to the plasma membrane. Changes in the abundance of the phosphate co-transporter NaPi-2a could explain the hyperphosphaturia in KO mice.
We also found that the surface expression of ClC-5 is influenced by HECT-ubiquitin ligases that bind through their WW-domains to a PY motif present in the carboxyterminal tail of ClC-5. In this project, we intend to further investigate the regulation of ClC-5 by ubiquitination and other factors and the impact of these processes on reabsorptive properties of the proximal tubule.

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