Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis

Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent's disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl-)/proton (H+) exchanger rather than a Cl- channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts CLC-5 into a pure CL- conductor. Adenosine triphosphate (ATP)-dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5unc mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by CLC-5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis.