VPLANS_DD_CLC-5 · ClC-5 regulation and endocytosis at the renal proximal tubule or molecular bases of Dents disease

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Project objective

Mutations in the gene encoding ClC-5, an electrogenic Cl-/H+-exchanger, cause a renal syndrome called Dents disease, which is characterized by genetic heterogeneity lowmolecular weight proteinuria, hypercalciuria, nephrolithiasis and progressive renal failure.By generating a ClC-5 knock out mouse, Thomas J. Jentsch and coworkers demonstrated that the loss of ClC-5 diminishes receptor-mediated and fluid-phase endocytosis. As ClC-5 provides an electrical shunt for the electrogenic pumping by the H+-ATPase, it is believed that the impaired acidification of endosomes causes the defect in endocytosis.However, other mechanisms such as direct protein-protein interactions in endosomes have not been excluded. The defective proximal tubular endocytosis is associated with an improper trafficking and/or downregulation of several key proteins for kidney physiology such as the megalin endocytotic receptor, NaPi-2 Na+-phosphate cotransporter and NHE3 Na+/H+ exchanger.Thus ClC-5 plays a major role in kidney physiology and serves as a paradigm to understand the role of vesicular acidification in endocytosis in general. The regulation of ClC-5 and its interaction with other proteins are poorly understood. However, it has been shown that ClC-5 interacts via a PY motif with certain HECT-ubiquitin ligases.I propose to further characterize the ubiquitylation of ClC-5 and to study the mechanisms by which it influences its localization and endocytosis. In addition, I would like to search for and test several putative interaction partners of ClC-5 in order to better understand the molecular bases of Dents disease and its genetic heterogeneity.

Original text from CORDIS.

Participants

• MAX-DELBRUCK-CENTRUM FUR MOLEKULARE MEDIZIN · BERLINCoordinatorCity levelGermany

Links

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